MDM2 Inhibitors

ABSTRACT

A compound capable of being used as a tumor inhibitor, a preparation method therefor, and application thereof. The compound has a structure represented by general formula I; a stereoisomer, an enantiomer, a raceme, a cis/trans isomer, a tautomer, and an isotopic variant of the compound are comprised; the compound can be used separately or in combination with other drugs for treating tumors or inflammatory diseases, or for treating other disorders or diseases mediated by the activity of MDM2 and/or MDM4, and shows prominent curative activity.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims the priority of the Chinese patent application for invention No. CN201711484280.8 filed on Dec. 29, 2017, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical preparations, in particular to a compound useful as a tumor inhibitor, and a preparation method therefor and use thereof.

BACKGROUND ART

P53 is a known tumor inhibition protein that plays an important role in growth inhibition and apoptosis of tumor cells. As a transcription factor, P53 can control the response of cells to DNA damage and prevent the proliferation of permanently damaged cells (controlled cell death) by triggering growth arrest, apoptosis, and senescence to maintain the normal function of cells.

However, in approximately 50% of tumors, P53 is inactivated due to gene mutation or deletion. In the remaining 50% of tumors, the function of P53 is regulated through a series of complex mechanisms, in which MDM2 acts as a negative regulator of P53, and has an important regulatory effect on the function of P53. In tumor cells, P53 is often inactivated due to overexpression of MDM2. Studies have found that about 10% of tumors have MDM2 amplification or overexpression phenomenon. In some specific tumors, this proportion is higher, for example, about 44% of liver cancers, 20% of osteosarcomas, and 31% of soft tissue sarcomas have MDM2 amplification or overexpression phenomenon. Therefore, inhibiting the negative regulatory effect of MDM2 in tumor cells on P53 can activate the P53 pathway, thereby inhibiting the proliferation of tumor cells and playing an antitumor role. MDM2 inhibitors that have been reported include RG7388, MI-773, HDM201 and the like.

However, considering the actual clinical needs, there is still an urgent need to develop other new compounds that can be used as tumor inhibitors.

SUMMARY OF THE INVENTION

Therefore, the purpose of the present invention is to overcome the defects in the prior art, to provide a compound that can be used as a tumor inhibitor, and a preparation method thereof and use thereof.

In a first aspect, the present invention provides a compound of structural formula I; or a stereoisomer, an enantiomer, a diastereomer, a racemate, a mesomer, a cis/trans isomer, a tautomer, an isotopic variant of the compound of structural formula I, or any combination thereof, or a pharmaceutical salt, a solvate, a hydrate, a polymorph or a prodrug of the compound of structural formula I, the stereoisomer, the enantiomer, the diastereomer, the racemate, the mesomer, the cis/trans isomer, the tautomer, the isotopic variant or their combination; or a hydrate of the pharmaceutical salt,

wherein, R₁ is selected from linear or branched alkyl or cycloalkyl having 1 to 5 carbon atoms, or

R₂ is selected from H, —(C₁-C₆ alkyl), wherein the alkyl is optionally substituted by 0 to 3 substituents, wherein the 0 to 3 substituents are independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

R₃ is selected from a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents, and the 1 to 3 substituents are independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or azetidin-1-yl substituted by one or more —OH or by both —CH₃ and —OH; wherein the alkyl or cycloalkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₃ is selected from a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents, and the 1 to 3 substituents are independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, azetidin-1-yl, or azetidin-1-yl substituted by one or more —OH or by both —CH₃ and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

or R₃ is selected from:

R₅ is selected from a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents, and the 1 to 3 substituents are independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, —CH₂CN, tetrahydropyrrol-1-yl, azetidin-1-yl, or azetidin-1-yl substituted by one or more —OH or by both —CH₃ and —OH; wherein the alkyl or cycloalkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₅ is selected from a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents, and the 1 to 3 substituents are independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, —CH₂CN, azetidin-1-yl, or azetidin-1-yl substituted by one or more —OH or by both —CH₃ and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

or R₅ is selected from:

R₆ is selected from halogen, halomethyl, methyl or cyano;

R₇ is selected from H, (C₁-C₆) alkyl, or halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ or methanesulfonyl;

wherein:

R₈ is selected from —OH, —OCH₃, —NH₂, —NHMe, —NMe₂, —NHCOMe, —NHCOH or methanesulfonyl;

R₉ is selected from H or alkyl having 1 to 4 carbon atoms;

R₁₀ is selected from H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl or methanesulfonyl;

R₁₁ is selected from —OCH₃, —CH₂CH₃, —OH, halomethoxy or H;

R₁₂ is selected from H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

R₁₃ is selected from halogen or alkyl having 1 to 4 carbon atoms;

R₁₄ is selected from H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ or methanesulfonyl;

R₁₅ is selected from NH₂, —C(O)OH, —NH(C(O)—CH₃) or —C(O)—NH(CH₃);

R₁₆ is selected from H, (C₁-C₆) alkyl or halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

R₁₇ is selected from —C(O)—NR₉(R₁₀), (C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl, and —C(O)O(C₁-C₆)alkyl; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; and/or

X₁ is selected from oxygen or sulfur; Y, X₂, V and W are each independently selected from carbon or nitrogen; when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —CN, halogen, —(C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀, or —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl or methanesulfonyl.

Preferably, the linear or branched alkyl or cycloalkyl having 1 to 5 carbon atoms in R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl or cyclopentyl;

the alkoxy in R₂ is selected from methoxy or ethoxy;

the haloalkyl in R₃ is halomethyl, preferably —CF₃, —CHF₂ or —CH₂F; the haloalkoxy in R₃ is selected from —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂ or —OCH₂CH₂F, and is preferably selected from —OCF₃, —OCHF₂, or —OCH₂F; the alkoxy in R₃ is selected from methoxy or ethoxy;

the haloalkyl in R₅ is halomethyl, preferably —CF₃, —CHF₂, or —CH₂F; the haloalkoxy in R₅ is selected from —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F, and is preferably selected from —OCF₃, —OCHF₂, or —OCH₂F; the alkoxy in R₅ is selected from methoxy or ethoxy;

the halogen in R₆ is selected from chlorine, fluorine or bromine; the halomethyl in R₆ is selected from trifluoromethyl, difluoromethyl or monofluoromethyl;

the alkoxy in R₇ is selected from methoxy or ethoxy;

the alkyl in R₉ is selected from methyl or ethyl;

the alkoxy in R₁₀ is selected from methoxy or ethoxy;

the halomethoxy in R₁₁ is selected from —OCF₃, —OCHF₂ or —OCH₂F;

the alkoxy in R₁₂ is selected from methoxy or ethoxy;

the alkyl in R₁₃ is selected from methyl or ethyl;

the alkoxy in R₁₄ is selected from methoxy or ethoxy;

the alkoxy in R₁₆ is selected from methoxy or ethoxy;

the alkoxy in R₁₇ is selected from methoxy or ethoxy; and

the alkoxy in R₄ is selected from methoxy or ethoxy.

Furthermore, in the compound of the present invention, preferably,

R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl or is:

R₂ is selected from H or methyl; preferably H;

R₃ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently selected from H, —(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₃ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, and —CH₂CN, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₃ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, and tetrahydropyrrol-1-yl;

R₅ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently preferably selected from H, —(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, —CH₂CN, and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₅ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently preferably selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, and —CH₂CN, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₅ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, and tetrahydropyrrol-1-yl;

R₆ is selected from chlorine or cyano; preferably chlorine;

R₇ is hydrogen;

X₁ is oxygen; X₂, V and W are all carbon; and/or

Y is nitrogen or carbon; when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀ or —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄) alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

wherein, R₉ is selected from H, methyl or ethyl;

R₁₀ is selected from H or (C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄) alkyl or methanesulfonyl.

In addition, as one of the preferred embodiments of the present invention: when Y is nitrogen, R₄ is not present; when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀ or —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl;

R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;

R₂ is H;

R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring, and the substituent is independently selected from H, —(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl or —NR₉R₁₀; wherein the alkyl or cycloalkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring, and the substituent is independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, or —NR₉R₁₀; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₃ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring or pyridazine ring, and the substituent is independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl or —NR₉R₁₀;

R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, and the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring; the substituent is independently selected from H, —(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl or —NR₉R₁₀; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, and the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring; the substituent is independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, or —NR₉R₁₀; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, or methanesulfonyl; preferably, R₅ is selected from a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring, and the substituent is independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl or —NR₉R₁₀;

R₆ is chlorine; R₇ is hydrogen; X₁ is oxygen; and/or X₂, V and W are all carbon;

wherein R₉ is selected from H, methyl or ethyl, and R₁₀ is selected from H, and —(C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, or methanesulfonyl; and R₁₀ is preferably H, methyl, ethyl, or 1-hydroxyethyl, more preferably H, methyl or ethyl.

Furthermore, as the most preferred embodiment of the present invention:

R₁ is selected from ethyl or isopropyl;

R₂ is H;

R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring, and the substituent is independently selected from H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, or —NR₉R₁₀;

when Y is nitrogen, R₄ is not present;

R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted by 1 to 3 substituents, the aromatic heterocycle is preferably pyridine ring, pyridone ring, pyrimidine ring, pyrazine ring, or pyridazine ring, and the substituent is independently selected from H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, or —C(O)NH₂;

R₆ is chlorine; R₇ is hydrogen;

X₁ is oxygen; Y is nitrogen; X₂, V, and W are all carbon;

wherein, R₉ is selected from H, methyl or ethyl, and R₁₀ is selected from H, methyl or ethyl.

More preferably, the compound according to the first aspect is one selected from the following structures:

Depending on the type or combination of substituents, the compounds represented by the general formula (I) of the present invention may have various isomers, for example, the isomers include, but are not limited to, stereoisomers (for example, “cis” and “trans” forms, enantiomers), tautomers and optical isomers (for example, dextrorotary and levorotary forms). Preferably, the compound of the present invention is in the S configuration to obtain a more ideal application activity. The compounds of the present invention also include all of these isomers, and mixtures of these isomers at any ratio, unless otherwise specified.

In addition, the present invention also includes a compound which is converted into compound (I) as an active ingredient of the pharmaceutical composition of the present invention due to reactions induced by enzymes, gastric acid and the like under physiological conditions in the body, that is, a compound which is converted into compound (I) by enzymatic oxidation, reduction, hydrolysis and the like, or a “pharmaceutically acceptable prodrug compound” which is converted into compound (I) by hydrolysis induced by gastric acid or the like.

Any structural formula given herein is also intended to represent the unlabeled form and isotope-labeled form of the compounds. An isotope-labeled compound or isotopic variant has the structure depicted by the structural formula given herein, except that one or more atoms are replaced by atom(s) having selected atomic mass or mass number. For example, the compound represented by the general formula (I) of the present invention may contain isotope(s) in an unnatural proportion as one or more constituent atom(s). Examples of isotopes include, but are not limited to, for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I), and carbon-14 (¹⁴C). These compounds are useful therapeutic or preventive agents, research reagents (for example, test reagents), and diagnostic agents (for example, in vivo diagnostic imaging agents). Regardless of the presence or absence of radioactivity, all isotopic variants of the compound represented by the general formula (I) are also included in the scope of the present invention.

The “pharmaceutically acceptable salt” in the present invention refers to an acid addition salt or a base addition salt of the compound of the present invention. “Salt” specifically includes “pharmaceutical salt”. The term “pharmaceutical salt” means a salt that retains the biological effectiveness and properties of the compound of the present invention, which is generally not biologically or otherwise undesirable. In many cases, the compound of the present invention can form acid and/or base salt(s) through the present amino and/or carboxyl or similar groups, for example, pharmaceutical acid addition salts can form the following salts with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphor sulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, glucoheptanoate, gluconate, glucuronate, hippurate, hydroiodate/iodide, hydroxyl ethyl sulfonate, lactate, lactobionate, dodecyl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthalene formate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

The pharmaceutical solvates of the present invention include those in which the crystalline solvent may be isotopically substituted, such as D₂O, d₆-acetone, and d₆-DMSO.

In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or contain other solvents for their crystallization. The compounds of the invention may form solvates inherently or by design with pharmaceutical solvents (including water); therefore, it means that the present invention includes both solvated and unsolvated forms. The term “solvate” means a molecular complex of the compound of the present invention (including a pharmaceutical salt thereof) with one or more solvent molecules. These solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, and the like. The term “hydrate” refers to a complex in which the solvent molecule is water. The compounds of the present invention, including their salts, hydrates, and solvates, can form polymorphs inherently or by design. Solvates or hydrates can be used to prepare crystalline forms of the compounds of formula (I).

In a second aspect, the present invention provides a preparation method of a plurality of the compounds of the first aspect as a preferred embodiment:

As a first parallel embodiment, when Y is N, the preparation method of the compound of the general formula I of the present invention comprises at least the following steps:

(1) compound 1 and compound 2 are subjected to a substitution and rearrangement reaction to synthesize compound 3;

(2) compound 3 and compound 4 are subjected to a cyclization reaction to construct an imidazole ring to obtain compound 5;

(3) compound 5 is brominated by NBS to obtain compound 6;

(4) compound 6 and compound 7 are subjected to low-temperature lithiation with LDA to obtain compound 8;

(5) compound 8 and compound 9 are subjected to an ammonolysis reaction to obtain compound 10;

(6) compound 10 is subjected to an acidification and dehydration reaction to obtain compound 11; and

(7) compound 11 and aryl or heteroaryl borate or boronic acid are subjected to a Suzuki coupling reaction to obtain product 12 (corresponding to the compound represented by the general formula (I));

wherein, R₁, R₂, R₃, R₅, R₆, R₇, X₁, X₂, V and W are as defined for the general formula I.

In the above-mentioned preparation method provided by the present invention, each step can be implemented by using various known reaction conditions. As a preferred embodiment, the present invention further defines each step as follows:

Step 1: preferably, the compound 2 is added dropwise to the compound 1 at 0±2° C., to react overnight at room temperature;

Step 2: preferably, cyclization reaction is performed at 70±2° C.;

Step 3: preferably, tetrahydrofuran is used as a solvent, and more preferably, NBS is added in batches at 0±2° C., followed by stirring overnight at room temperature;

Step 4: preferably, tetrahydrofuran is used as a solvent, and more preferably, the reaction is performed at −78±2° C. for 2 h;

Step 5: preferably, toluene is used as a solvent, more preferably, AlMe₃ and the compound 9 are added dropwise at 0±2° C., to react overnight at 90±2° C.;

Step 6: preferably, glacial acetic acid is used as a solvent, and reaction is performed under the action of concentrated sulfuric acid at 110±5° C. for 2 h;

Step 7: preferably, 1,4-dioxane and water are used as solvents, more preferably, Pd(PPh₃)₄ is used as a catalyst, sodium carbonate or potassium phosphate is used as a base, and a microwave reaction is performed at 100±2° C. for 1±0.5 h.

As a second parallel embodiment, when Y is C, the preparation method of the compound of the general formula I of the present invention comprises at least the following steps:

(1) compound 1 and compound 2 are subjected to a substitution reaction to synthesize compound 3;

(2) compound 3 is brominated by NBS to obtain compound 4;

(3) compound 4 and compound 5 are subjected to low-temperature lithiation with LDA to obtain compound 6;

(4) compound 6 and compound 7 are subjected to an ammonolysis reaction to obtain compound 8;

(5) compound 8 is subjected to an acidification and dehydration reaction to obtain compound 9; and

(6) compound 9 and aryl or heteroaryl boronic acid are subjected to a Suzuki coupling reaction to obtain product 11 (corresponding to the compound represented by the general formula (I));

wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇, X₁, X₂, V and W are as defined for the general formula I.; preferably X₁ is O.

In the above-mentioned preparation method provided by the present invention, each step can be implemented by using various known reaction conditions. As a preferred embodiment, the present invention further defines each step as follows:

wherein, step 1: preferably, at 0±2° C., DMF is used as a solvent, and the compound 2 is slowly added to the compound 1, to react overnight at room temperature;

Step 2: preferably, tetrahydrofuran is used as a solvent, NBS is added in batches at 0±2° C., followed by stirring overnight at room temperature;

Step 3: preferably, tetrahydrofuran is used as a solvent, and reaction is performed at −78±2° C. for 2±1 h;

Step 4: preferably, toluene is used as a solvent, AlMe₃ and compound 7 are added dropwise at 0±2° C., to react overnight at 90±2° C.;

Step 5: preferably, glacial acetic acid is used as a solvent, and reaction is performed under the action of concentrated sulfuric acid at 110±5° C. for 2±1 h;

Step 6: preferably, 1,4-dioxane and water are used as solvents, Pd(PPh₃)₄ is used as a catalyst, sodium carbonate or potassium phosphate is used as a base, and a microwave reaction is performed at 100±5° C. for 1±0.5 h.

Conventional conditions in the art can be used to carry out the reactions described in the above steps, which are not particularly limited in the present invention.

In a third aspect, the present invention provides a pharmaceutical composition comprising at least one compound as described in the first aspect above as an active ingredient.

The compounds described in the first aspect of the present invention may also be advantageously combined with one or more therapeutically active agents, preferably with one or more other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogen; topoisomerase I inhibitor; topoisomerase II inhibitor; microtubule active compounds; alkylating compounds; histone deacetylase inhibitor; compounds that induce cell differentiation processes; cyclooxygenase inhibitor; MMP inhibitor; mTOR inhibitors such as RAD001; antitumor antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity; and further anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies such as HCD122; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for treating blood cancer such as fludarabine; compounds that target, reduce or inhibit Flt-3 activity, such as PKC412; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, and CNF1010 and AUY922 of Conforma Therapeutics; temozolomide (TEMODAL™); kinesin spindle protein inhibitors such as SB715992 or SB743921 of GlaxoSmithKline, or pentamidine/chlorpromazine of CombinatoRx; PI3K inhibitors such as BEZ235; RAF inhibitors such as RAF265; MEK inhibitors such as ARRY142886 of Array PioPharma, AZD6244 of AstraZeneca, PD181461 of Pfizer, calcium folinate, EDG binding agents, anti-leukemic drug compounds, nucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, apoptosis regulators, antiproliferative antibodies, or other chemotherapeutic compounds. In addition, they may alternatively or additionally be used in combination with other tumor treatment methods including surgery, ionizing radiation, photodynamic therapy, implants, for example, with corticosteroids and hormones, or they may be used as radio sensitization agents. Moreover, in anti-inflammatory and/or anti-proliferative treatment, combinations with anti-inflammatory drugs are included. Combinations with antihistamines, bronchodilators, NSAID or chemokine receptor antagonists are also possible.

In addition to the active ingredient, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, and may be administered as various injections (such as intravenous injection, intramuscular injection, subcutaneous injection and the like), or administered by various methods (such as oral administration and transdermal administration). A pharmaceutically acceptable carrier refers to a pharmacologically acceptable material (for example, excipient, diluent, additive, solvent and the like) that involves transporting a compound of the present invention or a composition comprising a compound of the present invention from a given organ to another organ.

A formulation can be prepared by selecting an appropriate dosage form (for example, an oral formulation or an injection) according to the method of administration and using various methods for preparing the formulation. Examples of oral formulations include tablets, powders, granules, capsules, pills, lozenges, solutions, syrups, elixirs, emulsions, oily or aqueous suspensions, and the like. The present invention also provides the use of the compound described in the first aspect in the preparation of a medicament for treating diseases based on dysregulation of cell cycle.

Also provided is a method for treating a disease associated with MDM2 and P53 regulation, comprising administering to the patient an effective amount of the compound according to the first aspect of the present invention.

The compounds of the present invention are believed to be useful in the treatment of diseases based on dysregulation of cell cycle, such as proliferative disorders or diseases, such as cancers or tumor diseases. In particular, these diseases or disorders include benign or malignant tumors, soft tissue sarcomas or sarcomas such as a liposarcoma, a rhabdomyosarcoma or a bone cancer such as osteosarcoma, a brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, a glioblastoma, a meningioma, a glioma, a mesothelioma, a multiple myeloma, a gastrointestinal cancer, especially colon cancer or colorectal adenoma, head and neck tumors, a melanoma, a prostate hyperplasia, neoplasia, a neoplasia of epithelial character, a leukemia such as acute myeloid leukemia or B-cell chronic lymphocytic leukemia, lymphomas such as lymphoma of B- or T-cell origin, and other organ metastases, viral infections (such as herpes, papilloma, HIV, Kaposi's, viral hepatitis), and nephritis. Specific uses are for the treatment of benign or malignant tumors, soft tissue sarcomas or sarcomas such as a liposarcoma, a rhabdomyosarcoma or a bone cancer such as osteosarcoma, cancers such as a kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, a mesothelioma, a multiple myeloma, a gastrointestinal cancer, especially colon cancer or colorectal adenoma, head and neck tumors, a melanoma, a prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, leukemias such as acute myeloid leukemia or B-cell chronic lymphocytic leukemia, lymphomas such as lymphoma of B- or T-cell origin, and other organ metastases and nephritis.

Preferably, it can be used to treat a leukemia, a myeloma and a nephritis. The present invention also provides a method for treating diseases based on dysregulation of cell cycle, the method comprising administering an effective dose of the compound described in the first aspect or the composition described in the third aspect to a subject in need thereof by an oral or non-oral route.

The disease is preferably a tumor or nephritis disease; more preferably a disorder or disease mediated by the activity of MDM2 and/or MDM4.

The present invention also provides a method for treating diseases based on dysregulation of cell cycle, the method comprising administering an effective dose of the compound described in the first aspect or the composition described in the third aspect to a subject in need thereof by an oral or non-oral route.

The diseases based on dysregulation of cell cycle include cancer or tumor diseases. The tumor diseases include benign or malignant tumors.

Preferably:

the tumor disease include a soft tissue sarcoma or sarcoma, a leukemia or a bone cancer; preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; the leukemia is acute myeloid leukemia, chronic myeloid leukemia, or B-cell chronic lymphocytic leukemia; and the bone cancer is osteosarcoma.

The cancers include a brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, a glioblastoma, a meningioma, a glioma, a mesothelioma, a multiple myeloma, a gastrointestinal cancer; a especially colon cancer or colorectal adenomas, head and neck tumors, a melanoma, a prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, a leukemia, a lymphoma, and other organ metastases and viral infections.

More preferably, the leukemia is acute myeloid leukemia or B-cell chronic lymphocytic leukemia; the lymphoma is a lymphoma of B- or T-cell origin; the viral infection is herpes, papilloma, HIV, Kaposi's, or viral hepatitis.

Or, the disease of dysregulation of cell cycle is a disorder or disease involving immune system, preferably an autoimmune disease or immune disease caused by transplantation, a chronic inflammatory condition or an inflammatory or allergic condition of skin, or other skin inflammatory or allergic conditions or a hyperproliferativedisorder.

Preferably:

the autoimmune disease or immune disease caused by transplantation is rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, polymyositis.

The chronic inflammatory condition is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn.

The inflammatory or allergic condition of skin is psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes-like dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus, acquired epidermolysis bullosa.

The hyperproliferative disorder is Li-Fraumeni syndrome.

The present invention further provides a compound or composition for treating diseases based on dysregulation of cell cycle, the compound is the compound described in the first aspect.

The disease is preferably a tumor or nephritis disease; more preferably a disorder or disease mediated by the activity of MDM2 and/or MDM4.

The present invention further provides a compound or composition for treating diseases base on dysregulation of cell cycle, the compound is the compound described in the first aspect.

The diseases based on dysregulation of cell cycle include cancer or tumor diseases. The tumor diseases include benign or malignant tumors.

Preferably:

the tumor diseases include soft tissue sarcoma or sarcoma, leukemia or bone cancer; preferably, the sarcoma is liposarcoma or rhabdomyosarcoma; the leukemia is acute myeloid leukemia, chronic myeloid leukemia, or B-cell chronic lymphocytic leukemia; and the bone cancer is osteosarcoma.

The cancers include a brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer or thyroid cancer, a glioblastoma, a meningioma, a glioma, a mesothelioma, a multiple myeloma, a gastrointestinal cancer; especially colon cancer or colorectal adenomas, head and neck tumors, a melanoma, a prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, a leukemia, a lymphoma, and other organ metastases and viral infections.

More preferably, the leukemia is acute myeloid leukemia or B-cell chronic lymphocytic leukemia; the lymphoma is lymphoma of B- or T-cell origin; and the viral infection is herpes, papilloma, HIV, Kaposi's, or viral hepatitis.

Or, the disease of dysregulation of cell cycle is a disorder or disease involving immune system, preferably an autoimmune disease or immune disease caused by transplantation, a chronic inflammatory condition or an inflammatory or allergic condition of skin, or other skin inflammatory or allergic conditions or a hyperproliferativedisorder.

Preferably:

the autoimmune disease or immune disease caused by transplantation is rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, or polymyositis.

The chronic inflammatory condition is asthma, osteoarthritis, nephritis, atherosclerosis or Morbus Crohn.

The inflammatory or allergic condition of skin is psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes-like dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus, or acquired epidermolysis bullosa.

The hyperproliferative disorder is Li-Fraumeni syndrome.

In specific applications, the dosage and the interval of administration can be appropriately selected based on the judgment of a doctor and according to the location of the disease and the height, weight, sex, or medical history of the patient. When the compound of the present invention is administered to a human, the daily dose is about 0.01 to 500 mg/kg body weight, preferably about 0.1 to 100 mg/kg body weight. Preferably, the compound of the present invention is administered to a human once a day, or the dose is administrated in 2 to 4 divided doses at appropriate intervals. In addition, if necessary, the daily dose may exceed the above-mentioned dose based on the judgment of the doctor.

SPECIFIC MODES FOR CARRYING OUT THE EMBODIMENTS

The following Examples are used to illustrate the present invention, but not to limit the scope of the present invention.

All raw materials used in the present invention are known commercial products.

In the present invention, “Mdm2” refers to a protein encoded by the murine double minute 2 gene. “Mdm2” includes Mdm2 protein encoded by the full-length Mdm2 gene, Mdm2 protein encoded by mutated Mdm2 gene (including deletion mutants, substitution mutants, and addition mutants) and the like. In the present invention, “Mdm2” also includes homologs derived from different animal species, such as human Mdm2 homolog (HDM2).

The abbreviations and their meanings in the Examples of the present invention are as follows:

NBS: N-bromosuccinimide

EA: ethyl acetate

PE: petroleum ether

THF: tetrahydrofuran

LDA: lithium diisopropylamide

Pd(PPh₃)₄: tetrakis(triphenylphosphine)palladium

Example 1 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Step 1: Preparation of ethyl (E)-2-cyano-3-(dimethylamino)acrylate

Under nitrogen atmosphere, ethyl 2-isocyanate (500.0 g, 4.425 mol) and 1000 mL of ethanol were added to a 2000 mL three-necked flask, and cooled to −5° C., 1,1-diethoxy-N-methyl-N-methylene methanamine (845.6 g, 5.752 mol) was added dropwise. During the dropwise addition, the reaction solution was maintained at about 0° C., and then naturally raised to room temperature, stirred overnight, and concentrated under vacuum. The crude product was dissolved in 5 L of tert-butyl methyl ether, and the resultant mixture was added with 1 Kg of silica gel, stirred for 30 min and filtered. The filtrate was washed with 500 mL of tert-butyl methyl ether for 5 times, and concentrated under vacuum to obtain 678.2 g of ethyl (E)-2-cyano-3-(dimethylamino)acrylate (yield 91.25%, yellow oil). MS (ESI): mass calcd. for C₈H₁₂N₂O₂ 168.2, m/z found 169.3 [M+H]⁺.

Step 2: Preparation of ethyl 1-isopropyl-1H-imidazole-4-carboxylate

Under nitrogen atmosphere, ethyl (E)-2-cyano-3-(dimethylamino)acrylate (120.0 g, 0.714 mol), 100 mL of N-butanol and propyl-2-amine (126.4 g, 2.14 mol) were added to a 500 ml three-necked flask. The mixture was heated to 70° C. for overnight reaction and concentrated under vacuum. The resultant mixture was added with 1000 mL of ethyl acetate, and washed with 500 mL of saturated sodium chloride aqueous solution for three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 119.3 g of ethyl 1-isopropyl-1H-imidazole-4-carboxylate (yield 91.76%, brown oil). MS (ESI): mass calcd. For C₉H₁₄N₂O₂ 182.2, m/z found 183.4 [M+H]⁺.

Step 3: Preparation of ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate

Under nitrogen atmosphere, ethyl 1-isopropyl-1H-imidazole-4-carboxylate (60.0 g, 0.328 mol) and 500 mL of tetrahydrofuran were added to a 1000 mL three-necked flask, and cooled to 0° C., and NBS (87.0 g, 0.492 mol) was added in batches. The resultant was naturally raised to room temperature for overnight reaction, concentrated under vacuum, added with 500 mL of ethyl acetate, washed with 500 mL of saturated sodium carbonate aqueous solution for three times, then washed once with 45 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 21.2 g of ethyl 2-bromo-1-isopropyl-H-imidazole-4-carboxylate (yield 24.7%, yellow oil). MS (ESI): mass calcd. for C₉H₁₃BrN₂O₂ 260.0, m/z found 261.5 [M+H]⁺.

Step 4: Preparation of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate

Under nitrogen atmosphere, ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate (5.0 g, 19.15 mmol) and 10 mL of anhydrous THE were added to a 50 mL three-necked flask, and cooled to −78° C. LDA (40 ml, 2 M) was slowly added dropwise, and the resultant mixture was maintained at −78° C. to react for 1.5 h. Then an anhydrous tetrahydrofuran solution (100 ml) of 6-chlorodihydroindole-2,3-dione (3.46 g, 19.15 mmol) was slowly added dropwise. After the dropwise addition was completed, the mixture was maintained at −78° C. to react for 2 h, followed by quenching with 100 ml of saturated ammonium chloride aqueous solution, and extraction with 200 mL of ethyl acetate for three times. The organic layers were combined, washed once with 45 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 1.4 g of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate (yield 17.0%, yellow solid) as a yellow solid. MS (ESI): mass calcd. for C₁₇H₇BrClN₃O₄ 441.0, m/z found 442.0 [M+H]⁺.

Step 5: Preparation of 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide

Under nitrogen atmosphere, 3-chloroaniline (503.3 mg, 2.94 mmol) and 5 mL of anhydrous toluene were added to a 25 mL three-necked flask, and cooled to 0° C. AlMe₃ (1.2 ml, 25% w/w) was slowly added dropwise to the reaction solution, then 5 mL of anhydrous toluene solution of ethyl 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-imidazole-4-carboxylate (600 mg, 1.36 mmol) was slowly added dropwise into the reaction solution. The resultant mixture was raised to 90° C. for overnight reaction, then naturally lowered to room temperature, and added with 50 mL of ice water and 15 mL of saturated aqueous solution of sodium potassium tartrate, extracted with 100 mL of dichloromethane for two times. The organic layers were combined, washed once with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography to obtain 401.2 mg of 2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide (yield 56.47%, yellow solid). MS (ESI): mass calcd. for C₂₁H₁₇BrCl₂N₄O₃ 522.0, m/z found 523.4 [M+H]⁺.

Step 6: Preparation of 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

2-bromo-5-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-N-(3-chlorobenzene)-1-isopropyl-1H-imidazole-4-amide (400.0 mg, 0.766 mmol) and acetic acid (5 mL) were added to a 25 mL three-necked flask, concentrated sulfuric acid (0.75 g, 7.66 mmol) was added in batches, and the temperature was raised to 110° C. for reaction overnight, then the temperature was naturally lowered to room temperature, and 20 mL of ice water was added. The pH value was adjusted to 7.0 with saturated sodium carbonate aqueous solution, followed by extraction with 200 mL of dichloromethane for two times. The organic layers were combined, washed once with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and separated by column chromatography (EA:PE=1:5 to 1:1) to obtain 130.2 mg of 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (33.67% yield, yellow solid). MS (ESI): mass calcd. for C₂₁H₅BrCl₂N₄O₂ 504.0, m/z found 505.3 [M+H]⁺.

Step 7: Preparation of 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d] imidazole]-2,6′(5′H)-dione

Under nitrogen atmosphere, 2′-bromo-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (90.0 mg, 0.178 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (33.0 mg, 0.178 mmol), Pd(PPh₃)₄ (20.7 mg, 0.0178 mmol), anhydrous Na₂CO₃ (57.0 mg, 0.535 mmol), 1,4-dioxane (4 mL) and water (1 ml) were added into a microwave reaction flask, and then the temperature was raised to 100° C. to perform a microwave reaction for 1 h. The reaction solution was cooled to room temperature and filtered, and 10 mL of water was added, followed by extraction with 10 mL of dichloromethane for three times. The organic layers were combined, washed once with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, separated by column chromatography, and supercritical high-pressure preparative chromatography to obtain 7.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-1); and 8.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-1). MS (ESI): mass calcd. for C₂₇H₂₂Cl₂N₆O₄ 564.1, m/z found 565.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38-7.32 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.97 (m, 1H), 6.96-6.95 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 2 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.1 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-2); and 24.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-2).

MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₄ 578.1, m/z found 579.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.62 (brs, 1H), 8.53 (m, 1H), 7.51-7.41 (m, 4H), 6.98-6.89 (m, 2H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J=4.8 Hz), 0.67 (d, 3H, J=4.8 Hz).

Example 3 6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.1 mg of (S)-6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-3), and 35.8 mg of (R)-6-chloro-5′-(3-chloro-4-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-3). MS (ESI): mass calcd. for C₂₇H₂₁Cl₂FN₆O₄ 582.1, m/z found 583.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.55 (brs, 1H), 8.51 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.43-7.39 (m, 1H), 7.27 (dd, 1H, J=9.2 Hz, J²=2.4 Hz), 7.16-7.03 (m, 1H), 7.02-6.99 (m, 1H), 4.19-4.12 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 4 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.5 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-4); and 22.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-4). MS (ESI): mass calcd. for C₂₉H₂₃Cl₂FN₄O₃ 564.1, m/z found 565.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.47 (brs, 1H), 7.55-7.49 (m, 2H), 7.48-7.00 (m, 5H), 6.96-6.93 (m, 2H), 4.06-4.02 (m, 1H), 3.81 (s, 3H), 2.32 (s, 3H), 1.06 (d, 3H, J=5.2 Hz), 0.63 (d, 3H, J=5.2 Hz).

Example 5 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-5); and 13.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-5). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂N₄O₃ 546.1, m/z found 547.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.57-7.42 (m, 3H), 7.33-7.08 (m, 6H), 7.06-7.00 (m, 1H), 4.08-4.04 (m, 1H), 3.79 (s, 3H), 2.22 (s, 3H), 1.14 (d, 3H, J=5.2 Hz), 0.64 (d, 3H, J=5.2 Hz).

Example 6 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-6); and 18.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-6). MS (ESI): mass caled. for C₂₉H₂₃Cl₂FN₄O₃ 564.1, m/z found 565.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.61 (brs, 1H), 7.54-7.00 (m, 8H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 3.78 (s, 3H), 2.49 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 7 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-7), and 21.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethylphenyl)-3′-isopropylisopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-7). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₂ 544.1, m/z found 545.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.70 (brs, 1H), 7.60-6.95 (m, 10H), 6.97-6.96 (m, 1H), 4.07-4.04 (m, 1H), 2.45 (s, 3H), 1.11-1.07 (m, 8H), 0.67 (d, 3H, J=4.8 Hz).

Example 8 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-8), and 31.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-8). MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₄ 577.13, m/z found 578.2[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.82-7.80 (m, 1H), 7.79-7.04 (m, 6H), 6.56 (d, 2H, J=8.0 Hz), 4.13-4.10 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 9 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-9), and 18.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-9). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₄ 576.1 m/z found 577.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.58 (brs, 1H), 7.55-6.67 (m, 9H), 4.08-4.04 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.20 (s, 3H), 1.06 (d, 3H, J=4.0 Hz). 0.62 (d, 3H, J=4.0 Hz).

Example 10 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-34′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-10), and 28.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(3-methoxypyridin-4-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-10). MS (ESI): mass caled. for C₂₈H₂₃Cl₂N₅O₃ 547.1, m/z found 548.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.79 (brs, 1H), 8.61 (s, 1H), 8.40 (d, 1H, J=4.8 Hz), 7.62-7.45 (m, 2H), 7.33-6.98 (m, 5H), 4.11-4.10 (m, 1H), 4.08 (s, 3H), 2.22 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 11 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.6 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-11), and 17.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-11). MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₄ 577.1, m/z found 578.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.61 (brs, 1H), 8.13 (d, 1H, J=4.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.43-7.22 (m, 3H), 7.16-6.96 (m, 2H), 6.59 (d, 1H, J=1.6 Hz), 4.10-4.04 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.69 (d, 3H, J=6.4 Hz).

Example 12 4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.1 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (S-12), and 23.5 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (R-12). MS (ESI): mass calcd. for C₂₇H₂₂Cl₂N₆O₄ 564.1, m/z found 565.3[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H), 7.68-7.62 (m, 1H), 7.60-7.46 (m, 2H), 7.16-7.09 (m, 2H), 7.01-6.97 (m, 2H), 4.06-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 13 3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile (S-13), and 13.7 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzonitrile (R-13). MS (ESI): mass calcd. for C₃₀H₂₃Cl₂N₅O₃ 571.1, m/z found 572.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.06-8.04 (m, 2H), 7.97-6.97 (m, 7H), 4.05-4.02 (m, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 14 6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 54.9 mg of (S)-6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-14), and 50.8 mg of (R)-6-chloro-5′-(3-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-14). MS (ESI): mass calcd. for C₂₇H₂₁Cl₂FN₆O₄ 582.1, m/z found 583.5 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 8.54 (s, 1H), 7.59 (t, 1H, J=6.8 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.23-7.14 (m, 2H), 7.03-6.98 (m, 2H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 15 6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.5 mg of (S)-6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-15), and 54.6 mg of (R)-6-chloro-5′-(5-chloro-2-ethylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-15). MS (ESI): mass calcd. for C₂₉H₂₆Cl₂N₆O₄ 592.1, m/z found 593.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.38 (brs, 1H), 8.53 (d, 1H, J=6.8 Hz), 7.58-7.09 (m, 5H), 7.07-6.95 (m, 1H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.57-2.48 (m, 2H), 1.14-1.02 (m, 6H), 0.67 (d, 3H, J=6.0 Hz).

Example 16 6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 6.3 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-16), and 8.1 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-16). MS (ESI): mass calcd. for C₂₆H₂₁Cl₂N₇O₅ 581.1, m/z found 582.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.30 (brs, 1H), 8.51 (s, 1H), 7.97 (d, 1H, J=2.4 Hz), 7.31 (d, 1H, J=2.4), 7.21 (d, 1H, J=8.0), 7.04 (d, 1H, J=8.0), 6.99 (s, 1H), 4.13-4.08 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.35 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=8.0).

Example 17 6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.1 mg of (S)-6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-17), and 14.6 mg of (R)-6-chloro-5′-(5-chloro-2-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-17). MS (ESI): mass caled. for C₂₈H₂₄Cl₂N₆O₅ 594.1, m/z found 595.2[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.30-7.28 (m, 1H), 7.10 (s, 1H), 7.43-7.22 (m, 3H), 7.98-6.96 (m, 2H), 6.75-6.74 (m, 2H), 4.08-4.03 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.63 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 18 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.7 mg of(S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-18), and 30.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-18). MS (ESI): mass caled. for C₂₈H₂₃Cl₂N₅O₃ 547.1, m/z found 548.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.64 (d, 1H, J=5.6 Hz), 8.50 (d, 1H, J=6.0 Hz), 7.56-6.94 (m, 7H), 4.07-4.04 (m, 1H), 3.89 (s, 3H), 2.20 (s, 3H), 1.09 (d, 3H, J=7.2 Hz), 0.66 (d, 3H, J=7.2 Hz).

Example 19 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-19), and 24.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-5-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-19). MS (ESI): mass calcd. for C₃₂H₃₀Cl₂N₄O₃ 588.2, m/z found 589.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ, 7.59-6.89 (m, 9H), 4.06-4.03 (m, 1H), 3.83 (s, 3H), 2.63-2.59 (m, 1H), 2.22 (s, 3H), 1.23-1.15 (m, 6H), 0.83 (d, 3H, J=6.8 Hz), 0.65 (d. 3H, J=6.8 Hz).

Example 20 6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.0 mg of(S)-6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-20), and 27.9 mg of (R)-6-chloro-5′-(3-chloro-4-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-20). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₄ 578.1, m/z found 579.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.96 (brs, 1H), 7.94 (d, 1H, J=4.8 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.30 (d, 1H, J=8.0 Hz), 7.15 (dd, 1H, J¹=8.0 Hz, J²=1.6 Hz), 7.08-7.01 (m, 1H), 6.87 (d, 1H, J=8.0 Hz), 4.18-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.26 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 21 3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.4 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide (S-21), and 30.3 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N-methylbenzamide (R-21). MS (ESI): mass calcd. for C₃₁H₂₇Cl₂N₅O₄, 603.1 m/z found 604.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.46 (d, 1H, J=4.0 Hz), 8.08-8.06 (m, 1H), 7.96 (s, 1H), 7.55-6.99 (m, 6H), 4.08-4.04 (m, 1H), 3.86 (s, 3H), 2.77 (d, 3H, J=4.0 Hz), 2.23 (s, 3H), 1.07 (d, 3H, J=6.0 Hz), 0.65 (d, 3H, J=6.0 Hz).

Example 22 3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.9 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide (S-22), and 29.5 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxy-N,N-dimethylbenzamide (R-22). MS (ESI): mass caled. for C₃₁H₂₇Cl₂N₅O₄, 617.1 m/z found 618.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.66-6.97 (m, 9H), 4.09-4.06 (m, 1H), 3.85 (s, 3H), 2.98 (s, 6H), 2.22 (s, 3H), 1.08 (s, 3H), 0.65 (s, 3H).

Example 23 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-23), and 22.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-23). MS (ESI): mass calcd. for C₃₁H₂₉Cl₂N₅O₃ 589.2, m/z found 590.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.50 (brs, 1H), 7.51-6.38 (m, 9H), 4.12-4.09 (m, 1H), 3.77 (s, 3H), 3.00 (s, 6H), 2.22 (s, 3H), 1.06 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 24 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-24), and 26.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-24). MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₄O₃ 560.1, m/z found 561.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.54-6.91 (m, 9H), 4.08-4.04 (m, 1H), 3.77 (s, 3H), 2.39 (s, 3H), 2.22 (s, 3H), 1.06 (d, 3H, J=6.0 Hz), 0.63 (d, 3H, J=6.0 Hz).

Example 25 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-25), and 11.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(methylamine)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-25). MS (ESI): mass caled. for C₃₀H₂₇Cl₂N₅O₃ 575.2, m/z found 576.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 7.55-6.22 (m, 9H), 4.13-4.09 (m, 1H), 3.72 (s, 3H), 2.74 (s, 3H), 2.22 (s, 3H) 1.05 (d, 3H, J=5.2 Hz), 0.60 (d, 3H, J=5.2 Hz).

Example 26 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-26), and 28.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-ethyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-26). MS (ESI): mass caled. for C₂₇H₂₂Cl₂N₆O₄ 564.1, m/z found 565.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.54 (d, 1H, J=6.0 Hz), 7.64-6.95 (m, 6H), 3.99 (s, 3H), 3.95 (s, 3H), 3.58-3.50 (m, 1H), 2.25 (s, 3H), 1.17 (d, 3H, J=6.0 Hz), 0.85 (d, 3H, J=6.0 Hz).

Example 27 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 2.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-27), and 3.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-27). MS (ESI): mass caled. for C₂₇H₂₂Cl₂N₆O₃ 548.1, m/z found 549.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.19 (brs, 1H), 8.99 (s, 1H), 8.76 (d, 1H, J=7.2 Hz), 7.57-6.98 (m, 6H), 4.19-4.12 (m, 1H), 4.00 (s, 3H), 2.22 (s, 3H), 1.11 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=6.8 Hz).

Example 28 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-28), and 11.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropane-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-28). MS (ESI): mass calcd. for C₂₈H₂₂Cl₂N₆O₄ 576.1, m/z found 577.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.58 (brs, 1H), 8.55 (d, 1H, J=4.0 Hz), 7.56-6.97 (m, 6H), 3.99 (s, 3H), 3.96 (s, 3H), 3.01-3.00 (m, 1H), 2.23 (s, 3H), 0.85-0.47 (m, 4H).

Example 29 3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 6.1 mg of (S)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide (S-29), and 6.6 mg of (R)-3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzamide (R-29). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂N₅O₄ 589.1, m/z found 590.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.08 (d, 1H, J=6.8 Hz), 7.98 (brs, 2H), 7.37-6.52 (m, 8H), 4.02-3.96 (m, 1H), 3.84 (s, 3H), 2.26 (s, 3H), 1.10 (d, 3H, J=7.2 Hz), 0.66 (d, 3H, J=7.2 Hz).

Example 30 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-30), and 36.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(difluoromethoxy)phenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-30). MS (ESI): mass calcd. for C₂₉H₂₂Cl₂F₂N₄O₃ 582.1, m/z found 583.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.55 (brs, 1H), 7.69-6.96 (m, 10H), 4.08-4.07 (m, 1H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.67 (d, 3H, J=6.4 Hz).

Example 31 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-31), and 18.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-31). MS (ESI): mass calcd. for C₂₉H₂₁Cl₂F₃N₄O₃ 600.1, m/z found 601.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 7.77-6.96 (m, 10H), 4.10-4.03 (m, 1H), 2.22 (s, 3H), 1.09 (d, 3H, J=7.2 Hz), 0.70 (d, 3H, J=6.4 Hz).

Example 32 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-32), and 33.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-32). MS (ESI): mass calcd. for C₃₂H₃₀Cl₂N₄O₃ 588.2, m/z found 589.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.71 (brs, 1H), 7.56-6.48 (m, 9H), 4.08-4.05 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m, 1H), 2.22 (s, 3H) 1.27-1.23 (m, 6H), 1.07 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.8 Hz).

Example 33 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-33), and 20.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-33). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₃ 574.2, m/z found 575.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.70 (brs, 1H), 7.55-6.50 (m, 9H), 4.08-4.04 (m, 1H), 3.78 (s, 3H), 2.72-2.50 (m, 2H), 2.22 (s, 3H), 1.27-1.06 (m, 3H), 1.06 (d, 3H, J=6.4 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 34 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-34), and 21.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-34). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₃ 574.2, m/z found 575.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.67 (brs, 1H), 7.54-6.95 (m, 10H), 4.65-4.62 (m, 1H), 4.12-4.08 (m, 1H), 2.22 (s, 3H), 1.18 (m, 6H), 1.07 (d, 3H, J=7.2 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 35 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-35), and 23.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-35). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₃ 560.1, m/z found 561.5 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.68 (brs, 1H), 7.55-6.95 (m, 10H), 4.09-4.08 (m, 3H), 2.22 (s, 3H), 1.24 (t, 3H, J=6.0 Hz), 1.07 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 36 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-36), and 36.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-36). MS (ESI): mass caled. for C₂₉H₂₄C_(l2)N₄O₄ 562.1, m/z found 563.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.47-7.45 (m, 1H), 7.38-7.36 (m, 3H), 7.13-7.12 (m, 2H), 7.02 (s, 1H), 6.97 (d, 1H, J=7.2 Hz), 6.72-6.67 (m, 2H), 4.11-4.00 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.10 (d, 3H, J=5.2 Hz), 0.60 (d, 3H, J=5.2 Hz).

Example 37 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-37), and 32.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-37). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₃ 574.1, m/z found 575.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.70-6.98 (m, 9H), 4.08-4.05 (m, 1H), 3.76 (s, 3H), 2.64-2.60 (m, 2H), 2.22 (s, 3H), 1.23-1.17 (m, 3H), 1.07 (d, 3H, J=5.2 Hz), 0.63 (d, 3H, J=5.2 Hz).

Example 38 6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-38), and 23.1 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-38). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₃ 560.1, m/z found 561.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.39-7.32 (m, 3H), 7.15-7.10 (m, 3H), 7.01 (s, 1H), 6.98-6.96 (d, 1H, J=7.2 Hz), 4.10-4.04 (m, 1H), 3.75 (s, 3H), 2.64 (q, 2H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz), 1.10 (d, 3H, J=5.2 Hz), 0.61 (d, 3H, J=5.2 Hz).

Example 39 6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 8.0 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-39), and 12.7 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-39). MS (ESI): mass caled. for C₂₉H₂₄C_(l2)N₄O₄ 593.1, m/z found 594.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.44 (brs, 1H), 7.96 (d, 1H, J=2.4 Hz), 7.33-7.31 (m, 2H), 7.22 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 6.98 (s, 1H), 6.70-6.66 (m, 2H), 4.07-4.01 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.98 (m, 1H), 1.08 (d, 3H, J=6.4 Hz), 0.58 (d, 3H, J=6.4 Hz).

Example 40 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-40), and 28.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,5-dimethoxypyridin-4-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-40). MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₅O₄ 577.1, m/z found 578.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.62 (brs, 1H), 8.10 (s, 1H), 7.56-6.95 (m, 7H), 4.11-4.10 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.21 (s, 3H), 1.10 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 41 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-41), and 23.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclobutyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-41). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂N₆O₄ 590.1, m/z found 591.1 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-d₆) δ 11.38 (brs, 1H), 8.49 (d, 1H, J=5.4 Hz), 7.56-7.47 (m, 1H), 7.45-6.45 (m, 5H), 4.47-4.43 (m, 1H), 3.98-3.94 (m, 6H), 2.21 (s, 3H), 2.01-1.71 (m, 3H), 1.61-1.31 (m, 2H), 1.30-1.29 (m, 1H).

Example 42 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 8.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-42), and 8.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-42). MS (ESI): mass calcd. for C₂₇H₂₃Cl₂N₇O₄ 579.1, m/z found 580.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.53-8.46 (m, 2H), 7.61-6.96 (m, 4H), 4.17-4.13 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.40 (s, 1H), 0.84 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 43 6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.2 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-43), and 28.2 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-43). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂N₅O₄ 563.1, m/z found 564.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.95 (d, 1H, J=2.4 Hz), 7.56 (t, 1H, J=7.2 Hz), 7.41 (d, 1H, J=7.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 7.23-7.08 (m, 3H), 6.93 (s, 1H), 4.04-4.01 (m, 1H), 3.98 (s, 3H), 1.10 (d, 3H, J=5.4 Hz), 0.60 (d, 3H, J=5.4 Hz).

Example 44 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 15.4 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-44), and 19.7 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-44). MS (ESI): mass calcd. for C₂₇H₂₁Cl₂FN₆O₄ 582.1, m/z found 583.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.48-7.47 (m, 1H), 7.46-7.36 (m, 2H), 7.21-7.11 (m, 1H), 7.10-7.06 (m, 1H), 7.05-7.01 (m, 1H), 4.20-4.15 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.17 (d, 3H, J=6.8 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 45 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.1 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-45), and 29.8 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-45). MS (ESI): mass calcd. for C₂₇H₂₁Cl₂FN₆O₄ 582.1, m/z found 583.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.49-7.39 (m, 2H), 7.38-7.14 (m, 2H), 7.07-6.85 (m, 2H), 4.19-4.14 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 46 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-46), and 10.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-cyclopropyl-2′-(2,4-dimethoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-46). MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₆O₄, 604.1 m/z found 605.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (d, 1H, J=6.8 Hz), 7.50-6.48 (m, 7H), 4.32-4.27 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.21 (s, 3H), 1.92-1.91 (m, 1H), 1.69-1.67 (m, 1H), 1.37-1.23 (m, 4H), 0.91-0.80 (m, 2H).

Example 47 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-47), and 9.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((dimethylamino)methyl)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-47). MS (ESI): mass caled. for C₃₂H₃₁Cl₂N₅O₃ 603.2, m/z found 604.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.42-6.73 (m, 9H), 4.07-3.98 (m, 1H), 3.77 (s, 3H), 2.14 (s, 6H), 2.08 (s, 2H), 1.08 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.8 Hz).

Example 48 6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 32.4 mg of (S)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-48), and 34.4 mg of (R)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-48). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₅ 594.1, m/z found 595.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 8.51 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.14-7.07 (m, 3H), 6.97-6.92 (m, 2H), 4.16-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.81 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 49 2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.4 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-49), and 17.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-49). MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₅O₃, 561.1 m/z found 562.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.44-7.15 (m, 4H), 7.02-6.85 (m, 3H), 6.30 (s, 1H), 6.25 (d, 1H, J=8.0 Hz), 5.55 (brs, 2H), 4.24-4.06 (m, 1H), 3.67 (s, 3H), 2.22 (s, 3H), 1.06 (d, 1H, J=6.4 Hz), 0.61 (d, 1H, J=6.4 Hz).

Example 50 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

Step 1: Preparation of methyl 1-isopropyl-1H-pyrrole-3-carboxylate

Under nitrogen atmosphere, methyl 1H-pyrrole-3-carboxylate (25 g, 0.1998 mol) and 30 mL of anhydrous tetrahydrofuran were added to a 500 mL three-necked flask, and cooled to 0° C., NaH (7.19 g, 0.2997 mol) was added in batches, and the resultant mixture was maintained at 0° C. to react for 30 min, slowly and dropwise added with 2-bromopropane (49.2 g, 0.3996 mol), then naturally warmed to room temperature, and reacted overnight. The temperature was reduced to 0° C., and 20 mL of water was added dropwise for quenching, the resultant was concentrated under reduced pressure, added with 500 mL of ethyl acetate, and washed with 500 mL of saturated sodium carbonate aqueous solution for three times. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and separated by column chromatography (EA:PE=20% to 25%) to obtain 21.1 g of methyl 1-isopropyl-1H-pyrrole-3-carboxylate (yield 63.2%, yellow oil). MS (ESI): mass calcd. for C₉H₁₃NO₂ 167.1, m/z found 168.2[M+H]⁺.

Step 2 Preparation of methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate

Under nitrogen atmosphere, methyl 1-isopropyl-1H-pyrrole-3-carboxylate (5.0 g, 0.02994 mol) and 30 mL of anhydrous tetrahydrofuran were added to a 100 mL three-necked flask, and cooled to 0° C., and NBS (5.06 g, 0.0284 mol) was added in batches, the resultant was naturally warmed to room temperature to react overnight, concentrated under vacuum, added with 50 mL of ethyl acetate, then washed with 50 mL of saturated sodium carbonate aqueous solution for three times, the organic layer was dried over anhydrous sodium sulfate, and separated by column chromatography (EA:PE=5% to 25%) to obtain 5.8 g of methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (93% yield, yellow oil). MS (ESI): mass calcd. for C₉H₁₂BrNO₂ 245.0, m/z found 246.1[M+H]⁺.

Step 3: Preparation of methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindole-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate

Under nitrogen atmosphere, methyl 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylate (4.8 g, 0.0196 mol) and 20 mL of anhydrous tetrahydrofuran were added to a 100 mL three-necked flask, and cooled to −78° C. LDA (39.2 ml, 2 M) was slowly added dropwise, and the resultant was maintained at −50° C. to react for 1.5 h after completion of the dropwise addition. Then 6-chloroindolin-2,3-dione (3.546 g, 19.6 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and slowly added dropwise into the reaction flask, the resultant was maintained at −50° C. to react for 1 h. 10 mL of saturated ammonium chloride aqueous solution was added dropwise to the reaction flask, the resultant was concentrated under vacuum, added with 100 mL of ethyl acetate and washed once with 50 mL of saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (EA:PE=1:10 to 1:2) to obtain 1.2 g of methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindole-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate (yield 20%, yellow solid). MS (ESI): mass calcd. for C₁₇H₁₆BrCN₂O₄ 426.0, m/z found 409.0 [M+H−18]*.

Step 4: Preparation of 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide

Under nitrogen atmosphere, 5-chloro-2-methylaniline (450 mg, 3.169 mmol) and anhydrous toluene (5 mL) were added to a 50 mL reaction flask, the temperature was reduced to 0° C., and AlMe₃ (1.826 g, 25% w/w) was slowly added. Then, methyl 5-bromo-2-(6-chloro-3-hydroxy-2-oxoindol-3-yl)-1-isopropyl-1H-pyrrole-3-carboxylate (675 mg, 1.585 mmol) was dissolved in 5 mL of toluene, and slowly added dropwise into the reaction flask. The resultant mixture was warmed to 90° C. to react overnight, then cooled to room temperature, added with 20 mL of ice water and 15 mL of saturated aqueous solution of sodium potassium tartrate, then extracted with 50 mL of dichloromethane for two times. The organic phases were combined, washed once with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a preparative plate to obtain 795 mg of 5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide (94% yield, yellow solid). MS (ESI): mass calcd. for C₂₃H₂₀BrC₂N₃₃ 535.0, m/z found 518.0 [M+H−18]*.

Step 5: Preparation of 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

5-bromo-N-(5-chloro-2-methylphenyl)-2-(6-chloro-3-hydroxy-2-oxoindolin-3-yl)-1-isopropyl-1H-pyrrole-3-amide (1155 mg, 2.155 mmol), H₂SO₄ (2.112 g, 21.55 mmol) and acetic acid (10 mL) were added to a 50 mL reaction flask, and the temperature was raised to 110° C. for overnight reaction, then the temperature was naturally lowered to room temperature, and 20 mL of ice water was added. The pH value was adjusted to about 7 with saturated sodium carbonate aqueous solution, and the resultant was extracted with 50 mL of dichloromethane for two times. The organic layers were combined, washed once with 20 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA:PE=25%) to obtain 150 mg of 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (13.5% yield, yellow solid). MS (ESI): mass calcd. for C₂₃HisBrC₂N₃₂ 517.0, m/z found 518.0 [M+H]⁺.

Step 6: Preparation of 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione

Under nitrogen atmosphere, 2′-bromo-6-chloro-5′-(5-chloro-2-methylphenyl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (100 mg, 0.1934 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (36 mg, 0.1934 mmol), Pd(PPh₃)₄ (45 mg, 0.0387 mmol), Na₂CO₃ (62 mg, 0.5802 mmol), dioxane (4 mL) and H₂O (1 ml) were added into a microwave reaction flask, and the temperature was raised to 100° C. to perform a microwave reaction for 1 h. The resultant was cooled to room temperature, filtered, added with 10 mL of water, and extracted with 10 mL of dichloromethane for three times. The organic layers were combined, washed once with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a preparative plate, and then subjected to supercritical high-pressure preparative liquid phase separation to obtain 6.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (S-50); and 7.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-1′-isopropyl-1′H-spiro[dihydroindole-3,6′-pyrrolo[3,4-b]pyrrole]-2,4′(5′H)-dione (R-50). MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₅O₄ 577.1, m/z found 578.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.51 (d, 1H, J=8.0 Hz), 7.62-6.55 (m, 8H), 4.07 (s, 3H), 3.94 (s, 3H), 3.62-3.48 (m, 1H), 2.25 (s, 3H), 1.29 (d, 3H, J=6.4 Hz), 1.09 (d, 3H, J=6.4 Hz).

Example 51 6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those described in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.9 mg of (S)-6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-51), and 18.4 mg of (R)-6-chloro-5′-(3-chloro-5-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-51). MS (ESI): mass calcd. for: C₂₈H₂₄Cl₂N₆O₄, 579.4 m/z found 580.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.60 (brs, 1H), 8.51 (s, 1H), 7.46 (d, 1H, J=8.0 Hz), 7.18-7.13 (m, 2H), 7.02 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.20 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 52 6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.2 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-52), and 14.7 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-52). MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₅ 593.1, m/z found 594.3[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 7.55-7.51 (m, 2H), 7.49-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.02 (s, 1H), 6.71-6.66 (m, 2H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.32 (s, 3H), 1.07 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 53 6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.3 mg of (S)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-53), and 18.2 mg of (R)-6-chloro-5′-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-53). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂N₅O₄ 564.1, m/z found 565.3[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.49 (brs, 1H), 7.57-7.52 (m, 3H), 7.52-7.48 (m, 2H), 7.21-7.19 (m, 2H), 7.16-7.12 (m, 1H), 7.10-7.02 (m, 1H), 4.07-4.02 (m, 1H), 3.78 (s, 3H), 3.49 (s, 3H), 1.08 (d, 3H, J=6.8 Hz), 0.62 (d, 3H, J=6.8 Hz).

Example 54 4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.5 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide (S-54), and 8.8 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N-methylbenzamide (R-54). MS (ESI): mass caled. for C₃₁H₂₇Cl₂N₅O₄, 603.1 m/z found 604.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.59 (d, 1H, J=4.4 Hz), 7.59-6.94 (m, 9H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 2.83 (d, 3H, J=4.4 Hz), 2.23 (s, 3H), 1.08 (d, 3H, J=5.2 Hz). 0.64 (d, 3H, J=5.2 Hz).

Example 55 6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 52.7 mg of (S)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-55), and 58.7 mg of (R)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-5′-(m-tolyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-55). MS (ESI): mass calcd. for C₂₈H₂₅Cl₁N₆O₄ 544.2, m/z found 545.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.42 (d, 1H, J=8.0 Hz), 7.20-6.99 (m, 3H), 6.96 (s, 1H), 6.84 (s, 1H), 6.97 (d, 1H, J=8.0 Hz), 4.18-4.11 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.20 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 56 6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.4 mg of (S)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-56), and 48.7 mg of (R)-6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-5′-(2,5-dimethylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-56). MS (ESI): mass calcd. for C₂₉H₂₇ClN₆O₄ 558.1, m/z found 559.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 8.54 (d, 1H, J=7.6 Hz), 7.62-7.37 (m, 1H), 7.25-7.23 (m, 1H), 7.06-6.93 (m, 4H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.09 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.8 Hz).

Example 57 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-57), and 17.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-6-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-57). MS (ESI): mass calcd. for C₂₉H₂₃Cl₂FN₄O₃ 564.1, m/z found 565.1[M+H]⁺. ¹H-NMR (300 MHz, DMSO-d₆) δ 11.12 (brs, 1H), 7.62-6.97 (m, 9H), 4.01-3.98 (m, 1H), 3.82 (s, 3H), 2.23 (s, 3H), 1.07-1.02 (m, 3H), 0.70-0.63 (m, 3H).

Example 58 6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.3 mg of (S)-6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-58), and 29.9 mg of (R)-6-chloro-5′-(3-chloro-5-methoxyphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-58). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₅ 594.1, m/z found 595.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.65 (brs, 1H), 8.51 (s, 1H), 7.47 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=1.6 Hz), 6.95 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 4.16-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.67 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 59 6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.9 mg of (S)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-59), and 22.5 mg of (R)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-2′-(4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-59). MS (ESI): mass calcd. for: C₂₇H₂₀Cl₂FN₅O₃, 551.1 m/z found 552.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.64 (d, 1H, J=6.4 Hz), 8.48 (brs, 1H), 7.54 (d, 1H, J=8.0 Hz), 7.44-7.42 (m, 1H), 7.40-7.14 (m, 4H), 7.08-6.97 (m, 2H), 4.09-4.03 (m, 1H), 3.88 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 60 2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 14.0 mg of (S)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (S-60), and 16.3 mg of (R)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (R-60). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂N₇O₅ 607.1, m/z found 608.1 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.16-7.14 (m, 2H), 7.06-6.99 (m, 2H), 4.17-4.14 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.13 (d, 3H, J=6.4 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 61 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-61), and 26.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-61). MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₄ 577.1, m/z found 578.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.4 Hz), 7.54 (d, 1H, J=9.2 Hz), 7.36-7.33 (m, 1H), 7.27 (d, 1H, J=8.0 Hz), 7.04-7.00 (m, 1H), 6.73-6.79 (m, 2H), 4.10 (t, 1H, J=6.8 Hz), 3.84 (s, 3H), 3.79 (s, 3H), 2.42-2.27 (m, 3H), 1.07 (d, 3H, J=4.8 Hz), 0.638 (d, 3H, J=4.8 Hz).

Example 62 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-62), and 44.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-5-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-62). MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₄O₃, 560.1 m/z found 561.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.72 (brs, 1H), 7.55-6.97 (m, 10H), 4.09-4.05 (m, 1H), 3.75 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=5.6 Hz), 0.63 (d, 3H, J=5.6 Hz).

Example 63 6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.9 mg of (S)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-63), and 22.9 mg of (R)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-2′-(2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-63). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂N₄O₄, 563.4 m/z found 564.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.57-6.91 (m, 10H), 4.08-4.00 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.08 (m, 3H), 0.75-0.70 (m, 3H).

Example 64 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 73.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-64), and 79.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-64). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂N₄O₃ 546.1, m/z found 547.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 7.58-6.45 (m, 10H), 4.46-4.43 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.11-1.09 (d, 3H, J=6.4 Hz), 0.75 (d, 3H, J=6.4 Hz).

Example 65 2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.3 mg of (S)-2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (S-65), and 10.3 mg of (R)-2-chloro-4-(6-chloro-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzamide (R-65). MS (ESI): mass caled. for C₂₉H₂₄Cl₂N₆O₅ 606.1, m/z found 607.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.63 (brs, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.16-7.14 (m, 2H), 7.04-7.01 (m, 1H), 7.01-6.99 (m, 1H), 6.59 (s, 1H), 4.07-4.03 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 66 2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 12.7 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-66), and 10.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-66). MS (ESI): mass calcd. for C₂₈H₂₂Cl₂FN₅O₃ 565.1, m/z found 566.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.70-7.00 (m, 7H), 6.31 (s, 1H), 6.23 (d, 1H, J=9.2 Hz), 5.59 (brs, 2H), 4.12-4.07 (m, 1H), 3.67 (s, 3H), 1.07 (d, 3H, J=5.6 Hz), 0.60 (d, 3H, J=5.6 Hz).

Example 67 2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 21.3 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-67), and 18.8 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-5-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-67). MS (ESI): mass calcd. for C₂₈H₂₂Cl₂FN₅O₃ 565.1, m/z found 566.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.35-7.28 (m, 2H), 7.02-6.92 (m, 5H), 6.29 (s, 1H), 6.24 (d, 1H, J=8.0 Hz), 5.57 (brs, 2H), 4.10-4.04 (m, 1H), 3.65 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.57 (d, 3H, J=6.4 Hz).

Example 68 4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.4 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide (S-68), and 17.1 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxy-N,N-dimethylbenzamide (R-68). MS (ESI): mass calcd. for C₃₂H₂₉Cl₂N₅O₄, 617.2 m/z found 618.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 7.58-6.97 (m, 9H), 4.10-4.07 (m, 1H), 3.82 (s, 3H), 3.01 (s, 3H), 2.96 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 69 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-69), and 28.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-69). MS (ESI): mass calcd. for C₃₁H₂₉Cl₂N₅O₄, 605.2 m/z found 606.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 8.10 (d, J=4.4 Hz, 1H), 7.56-6.96 (m, 7H), 5.36-5.30 (m, 1H), 4.08-4.05 (m, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.33 (d, J=6.4 Hz, 6H), 1.08 (d, J=5.2 Hz, 3H), 0.64 (d, J=5.2 Hz, 3H).

Example 70 2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.9 mg of (S)-2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (S-70), and 30.7 mg of (R)-2-(3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxyphenyl)-N,N-dimethylacetamide (R-70). MS (ESI): mass caled. for C₃₃H₃₁Cl₂N₅O₄ 631.2, m/z found 632.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.72 (brs, 1H), 7.57-6.96 (m, 9H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 3.69 (s, 2H), 3.01 (s, 3H), 2.83 (s, 3H), 2.22 (s, 3H), 1.07 (s, 3H), 0.36 (s, 3H).

Example 71 2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.1 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-71), and 16.1 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-71). MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₄, 577.1 m/z found 578.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.20-6.20 (m, 9H), 5.49 (s, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 1.11-1.05 (m, 3H), 0.60-0.59 (m, 3H).

Example 72

6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-72), and 23.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-72). MS (ESI): mass calcd. for C₃₀H₂₇Cl₂N₅O₄ 591.1, m/z found 592.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.10 (s, 1H), 7.56-7.44 (m, 1H), 7.31-6.48 (m, 6H), 4.40 (brs, 2H), 4.06-4.02 (m, 1H), 3.84 (s, 3H), 2.21 (s, 3H), 1.36 (t, 3H, J=7.6 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 73 2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 24.7 mg of (S)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-73), and 28.7 mg of (R)-2′-(4-amino-2-methoxyphenyl)-6-chloro-5′-(3-chloro-4-fluorophenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-73). MS (ESI): mass caled. for C₂₈H₂₂Cl₂FN₅O₃ 565.1, m/z found 566.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.39-7.34 (m, 1H), 7.27-7.21 (m, 2H), 7.03-6.90 (m, 4H), 6.29 (s, 1H), 6.24 (d, 1H, J=8.0 Hz), 5.56 (brs, 2H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 1.08 (s, 3H), 0.59 (s, 3H).

Example 74 2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.0 mg of (S)-2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-74), and 26.6 mg of (R)-2′-(4-amino-2-methoxy-5-methylphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-74). MS (ESI): mass caled. for C₃₀H₂₇Cl₂N₅O₃ 575.1, m/z found 576.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.68 (brs, 1H), 7.51-6.93 (m, 8H), 5.33 (brs, 2H), 4.12-4.10 (m, 1H), 3.66 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.05 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 75 2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.8 mg of (S)-2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-75), and 12.7 mg of (R)-2′-(4-amino-5-fluoro-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-75). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂FN₅O₃ 579.1, m/z found 580.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 7.49-6.46 (m, 8H), 5.65 (brs, 2H), 4.13-4.11 (m, 1H), 3.67 (s, 3H), 2.21 (s, 3H), 1.06 (s, 3H, J=6.0 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 76 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 22.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-76), and 25.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(3-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-76). MS (ESI): mass calcd. for C₂₉H₂₃Cl₂FN₄O₃ 564.1, m/z found 565.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.51 (brs, 1H), 7.57-6.95 (m, 9H), 4.11-4.10 (m, 1H), 3.77 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 77 4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.6 mg of (S)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide (S-77), and 21.5 mg of (R)-4-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzamide (R-77). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂N₅O₄, 589.1 m/z found 590.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.76 (brs, 1H), 8.14 (brs, 2H), 7.64-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.85 (s, 3H), 2.22 (s, 3H), 1.07 (d, 3H, J=4.8 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 78 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-78), and 28.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-dimethylamino)-5-fluoro-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-78). MS (ESI): mass caled. for C₃₁H₂₈Cl₂FN₅O₃ 607.2, m/z found 608.2 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 7.52-6.57 (m, 9H), 4.12-4.10 (m, 1H), 3.78 (s, 3H), 2.91 (s, 6H), 2.21 (s, 3H), 1.06 (d, 3H, J=4.0 Hz), 0.63 (d, 3H, J=4.0 Hz).

Example 79 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-79), and 24.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-79). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₄ 576.1, m/z found 577.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.70 (brs, 1H), 7.51-6.78 (m, 9H), 3.90-3.83 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.24 (s, 3H), 1.02 (d, 3H, J=6.8 Hz), 0.61 (d, 3H, J=6.8 Hz).

Example 80 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 32.0 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-80), and 35.4 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-80). MS (ESI): mass caled. for C₂₉H₂₃Cl₂FN₄O₄ 580.1, m/z found 581.2 [M+H]⁺. 1H-NMR (400 MHz, DMSO-d₆) δ 11.85 (brs, 1H), 7.48-6.66 (m, 9H), 4.09-4.03 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.04 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 81 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 26.0 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-81), and 19.5 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-81). MS (ESI): mass caled. for C₃₀H₂₆Cl₂FN₅O₃ 593.13, m/z found 594.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.46-7.05 (m, 6H), 6.98 (s, 1H), 6.40 (d, 1H, J=8.4 Hz), 6.35 (s, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 2.99 (s, 6H), 1.08 (d, 3H, J=5.6 Hz), 0.61 (d, 3H, J=5.6 Hz).

Example 82 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-82), and 13.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-82). MS (ESI): mass calcd. for C₂₉H₂₇Cl₂N₇O₃ 591.15, m/z found 592.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.25 (d, 1H, J=4.4 Hz), 7.55-6.97 (m, 6H), 4.15-4.12 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.20 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 83 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 48.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-83), and 30.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-83). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₄ 590.19, m/z found 591.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.47-7.04 (m, 6H), 6.98 (d, 1H, J=1.6 Hz), 6.40 (d, 1H, J=8.4 Hz), 6.35 (s, 1H), 4.12-4.08 (m, 1H), 3.76 (s, 3H), 2.99 (s, 6H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 84 3-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxybenzoic acid

80 mg of the title compound was obtained by steps similar to those in Example 1. MS (ESI): mass calcd. for C₃₀H₂₄Cl₂N₄O₅, 590.11 m/z found 591.1 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.35 (brs, 1H), 8.12 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 7.60-6.97 (m, 7H), 4.07-4.06 (m, 1H), 3.87 (s, 3H), 2.23 (s, 3H), 1.17 (d, 3H, J=7.2 Hz), 0.62 (d, 3H, J=7.2 Hz).

Example 85 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-85), and 9.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-85). MS (ESI): mass caled. for C₃₀H₂₃Cl₂F₃N₄O₃ 614.11, m/z found 615.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.71-6.98 (m, 9H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.18 (d, 3H, J=4.0 Hz), 0.64 (d, 3H, J=4.0 Hz).

Example 86 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 18.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-86), and 21.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-86). MS (ESI): mass calcd. for C₃₂H₂₈Cl₂N₄O₃ 586.15 m/z found 587.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 7.53-6.47 (m, 9H), 4.07-4.03 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H), 2.01-2.00 (m, 1H), 1.16 (d, 3H, J=6.4 Hz), 1.05-1.00 (m, 4H), 0.64 (d, 3H, J=6.4 Hz).

Example 87 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-87), and 44.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-87). MS (ESI): mass calcd. for C₃₀H₂₃Cl₂F₃N₄O₄, 630.10 m/z found 631.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.74 (brs, 1H), 7.60-6.48 (m, 9H), 4.07-4.02 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H), 1.14 (d, 3H, J=4.8 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 88 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-88), and 42.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-88). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₄ 590.15 m/z found 591.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 7.54-6.95 (m, 9H), 4.14-4.04 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 1.36 (t, 3H, J=6.8 Hz), 1.05 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 89 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-89), and 32.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-89). MS (ESI): mass calcd. for C₃₁H₂₉Cl₂N₅O₃ 589.16, m/z found 590.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 7.64-7.00 (m, 7H), 4.09-4.06 (m, 1H), 3.79 (s, 3H), 3.01-2.94 (m, 1H), 2.42 (s, 3H), 1.35 (d, 3H, J=7.6 Hz), 1.27 (d, 3H, J=7.6 Hz), 1.07 (d, 3H, J=4.0 Hz), 0.64 (d, 3H, J=4.0 Hz).

Example 90 2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.0 mg of (S)-2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-90), and 17.4 mg of (R)-2′-(2-amino-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-90). MS (ESI): mass calcd. for C₂₇H₂₃Cl₂N₇O₃ 563.12, m/z found 564.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 8.14 (d, 1H, J=4.8 Hz), 7.54-6.96 (m, 8H), 4.18-4.13 (m, 1H), 3.84 (s, 3H), 2.20 (s, 3H), 1.08 (d, 3H, J=4.4 Hz), 0.67 (d, 3H, J=4.4 Hz).

Example 91 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-91), and 17.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxy-5-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-91). MS (ESI): mass calcd. for C₃₂H₃₁Cl₂N₅O₃ 603.18, m/z found 604.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.51 (brs, 1H), 7.53-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.77 (s, 3H), 2.73 (s, 6H), 2.22 (s, 3H), 2.07 (s, 3H), 1.06 (d, 3H, J=4.4 Hz), 0.62 (d, 3H, J=4.4 Hz).

Example 92 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 29.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-92), and 33.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(5-fluoro-2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-92). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂FN₄O₄ 594.13, m/z found 595.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.75 (brs, 1H), 7.53-6.47 (m, 8H), 4.10-4.07 (m, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 2.21 (s, 3H), 1.07 (d, 3H, J=4.4 Hz), 0.63 (d, 3H, J=4.4 Hz).

Example 93 6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 125.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-93), and 132.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-93). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₃ 574.15, m/z found 575.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.58 (brs, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38-6.95 (m, 9H), 4.09-4.02 (m, 1H), 3.78 (s, 3H), 3.01-2.94 (m, 1H), 1.27 (d, 6H, J=7.2 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.59 (d, 3H, J=6.4 Hz).

Example 94 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 7.8 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-94), and 15.2 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-94). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂FN₄O₄ 594.12, m/z found 595.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.01 (brs, 1H), 7.48-6.64 (m, 9H), 4.14-4.04 (m, 3H), 3.76 (s, 3H), 1.37-1.18 (m, 3H), 1.04 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 95 6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 100.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-95), and 108.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-95). MS (ESI): mass caled. for C₃₀H₂₇Cl₂N₅O₄ 591.14, m/z found 592.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.53 (brs, 1H), 8.08 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=9.2 Hz), 7.00 (d, 1H, J=1.6 Hz), 6.97 (d, 1H, J=7.2 Hz), 6.51 (s, 1H), 5.36-5.29 (m, 1H), 4.11-4.04 (m, 1H), 3.82 (s, 1H), 1.33 (d, 6H, J=6.0 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.4 Hz).

Example 96 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-96), and 29.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-96). MS (ESI): mass calcd. for C₂₉H₂₆Cl₂N₆O₄ 592, m/z found 593.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.80 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 8.12 (d, 1H, J=4.8 Hz), 7.64-7.00 (m, 4H), 6.58 (s, 1H), 4.40 (q, 2H, J=7.2 Hz), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 2.27 (s, 3H), 1.36 (t, 3H, J=7.2 Hz), 1.08 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 97 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 0.8 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-97), and 3.3 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-97). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂FN₆O₄ 596.11, m/z found 597.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.59 (brs, 1H), 8.51 (s, 1H), 7.48-7.00 (m, 6H), 4.46 (q, 2H, J=6.8 Hz), 4.10-4.07 (m, 1H), 3.94 (s, 3H), 1.39 (t, 3H, J=6.8 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 98 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.5 mg of(S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-98), and 20.7 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-98). MS (ESI): mass caled. for C₂₉H₂₄Cl₂FN₅O₄ 595.11, m/z found 596.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.60 (brs, 1H), 8.11 (s, 1H), 7.48-7.00 (m, 6H), 6.57 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.08-4.04 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 99 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-99), and 41.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(ethyl(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-99). MS (ESI): mass calcd. for C₃₂H₃₁Cl₂N₅O₃ 603, m/z found 604.2[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 7.54-6.96 (m, 7H), 6.46-6.32 (m, 2H), 4.11-4.10 (m, 1H), 3.76 (s, 3H), 3.47-3.45 (m, 2H), 2.95 (s, 3H), 2.21 (s, 3H), 1.11-1.07 (m, 6H), 0.62 (d, 3H, J=6.4 Hz).

Example 100 6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-100), and 21.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethoxy-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-100). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₄ 576.13, m/z found 577.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.56 (brs, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.37-6.94 (m, 7H), 6.69 (s, 1H), 6.66 (d, 1H, J=8.4 Hz), 7.00-6.94 (m, 2H), 4.14-4.03 (m, 3H), 3.76 (s, 3H), 1.37 (t, 3H, J=6.8 Hz), 1.04 (d, 3H, J=6.4 Hz), 0.60 (d, 3H, J=6.4 Hz).

Example 101 2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.1 mg of (S)-2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-101), and 17.2 mg of (R)-2′-(4-(tert-butyl)-2-methoxyphenyl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-101). MS (ESI): mass calcd. for C₃₃H₃₂Cl₂N₄O₃ 602.2, m/z found 603.4 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 7.56-6.48 (m, 9H), 4.08-4.07 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.35 (s, 9H), 1.07 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 102 6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-prrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 53.4 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-102), and 55.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-102). MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₅O₄ 577.13, m/z found 578.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 8.09 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.14-7.12 (m, 2H), 7.00 (s, 1H), 6.97 (d, 1H, J=7.2 Hz), 6.57 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 103 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 39.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-103), and 32.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-103). MS (ESI): mass calcd. for C₃₁H₂₇Cl₂N₅O₃ 587, m/z found 588.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.72 (brs, 1H), 8.30 (d, 1H, J=4.0 Hz), 7.57-6.97 (m, 7H), 4.08-4.06 (m, 2H), 3.88 (s, 3H), 2.21 (s, 3H), 2.07-1.98 (m, 4H), 1.08 (d, 3H, J=6.0 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 104 6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 80.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-104), and 70.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-104). MS (ESI): mass caled. for C₃₀H₂₇C_(l2)N₅O₃ 575.15, m/z found 576.6[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.50 (brs, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.37-7.30 (m, 2H), 7.17-7.11 (m, 3H), 7.00-6.94 (m, 2H), 6.40-6.35 (m, 2H), 4.13-4.06 (m, 1H), 4.06 (s, 3H), 3.76 (s, 3H), 2.99 (s, 6H), 1.09 (d, 3H, J=6.0 Hz), 0.60 (d, 3H, J=6.0 Hz).

Example 105 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 11.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-105), and 16.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(diethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-105). MS (ESI): mass caled. for C₃₃H₃₃Cl₂N₅O₃ 617.19, m/z found 618.5 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.68 (brs, 1H), 7.54-6.94 (m, 7H), 6.46-6.27 (m, 2H), 4.14-4.11 (m, 1H), 3.75 (s, 3H), 3.42-3.40 (m, 4H), 2.21 (s, 3H), 1.16-1.12 (m, 6H), 1.06 (d, 3H, J=5.2 Hz), 0.62 (d, 3H, J=5.2 Hz).

Example 106 6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 47.4 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-106), and 57.5 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-106). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂N₅O₃ 573, m/z found 574.3[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.56 (brs, 1H), 8.33 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.36-6.95 (m, 8H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 2.15-2.00 (m, 1H), 1.05 (d, 3H, J=6.0 Hz), 1.03-0.98 (m, 4H), 0.62 (d, 3H, J=6.0 Hz).

Example 107 6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 49.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-107), and 39.8 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-107). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₄O₃ 560.13, m/z found 561.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.48 (brs, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.37-6.94 (m, 9H), 4.09-4.02 (m, 1H), 3.77 (s, 3H), 2.72 (q, 2H, J=7.6 Hz), 1.26 (t, 3H, J=7.6 Hz), 1.04 (d, 3H, J=6.0 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 108 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-108), and 29.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-cyclopropyl-2,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-108). MS (ESI): mass calcd. for C₃₃H₃₀Cl₂N₄O₄ 616.16, m/z found 617.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.66 (brs, 1H), 7.45-6.48 (m, 8H), 3.89-3.88 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 2.23 (s, 3H), 2.07-2.00 (m, 1H), 1.01-0.99 (m, 5H), 0.84-0.83 (m, 2H), 0.60 (d, 3H, J=6.8 Hz).

Example 109 6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 34.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-108), and 43.5 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-methylphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-108). MS (ESI): mass caled. for C₂₉H₂₄Cl₂N₄O₃ 546.12, m/z found 547.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.53 (brs, 1H), 7.47-6.90 (m, 10H), 4.07-4.02 (m, 1H), 3.76 (s, 3H), 2.39 (s, 3H), 1.04 (d, 3H, J=6.0 Hz), 0.59 (d, 3H, J=6.0 Hz).

Example 110 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-109), and 13.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-109). MS (ESI): mass calcd. for C₃₁H₂₇Cl₂N₅O₄ 603.14, m/z found 604.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.16-6.48 (m, 8H), 4.31-4.30 (m, 1H), 4.07-4.06 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=5.6 Hz), 0.82-0.80 (m, 2H), 0.79-0.71 (m, 2H), 0.65 (d, 3H, J=5.6 Hz).

Example 111 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 44.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-110), and 47.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-110). MS (ESI): mass calcd. for C₂₉H₂₇Cl₂N₇O₃ 591, m/z found 592.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 7.98-6.21 (m, 8H), 4.11-4.07 (m, 1H), 3.84 (s, 3H), 3.10 (s, 6H), 2.22 (s, 3H), 1.07 (d, 3H, J=6.0 Hz), 0.63 (d, 3H, J=6.0 Hz)

Example 112 6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.9 mg of(S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-111), and 46.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-111). MS (ESI): mass caled. for C₂₈H₂₅Cl₂N₇O₃ 577.13, m/z found 578.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.52 (brs, 1H), 8.23 (s, 1H), 7.65-6.94 (m, 7H), 4.16-4.09 (m, 1H), 3.89 (s, 3H), 3.19 (s, 6H), 1.11 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 113 6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.0 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-112), and 34.4 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-112). MS (ESI): mass calcd. for C₂₉H₂₆Cl₂N₆O₃ 576, m/z found 577.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.60 (brs, 1H), 8.06 (s, 1H), 7.44-6.96 (m, 7H), 6.39 (s, 1H), 4.12-4.05 (m, 1H), 3.92 (s, 3H), 3.20 (s, 6H), 1.12 (d, 3H, J=6.8 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 114 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 10.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-113), and 13.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-113). MS (ESI): mass calcd. for C₃₁H₂₉Cl₂N₇O₃ 617.17, m/z found 618.2[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.63 (brs, 1H), 8.24 (d, 1H, J=4.4 Hz), 7.54-6.47 (m, 6H), 4.13-4.12 (m, 1H), 3.90 (s, 3H), 3.69-3.56 (m, 4H), 2.21 (s, 3H), 2.06-1.95 (m, 4H), 1.09 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=6.0 Hz).

Example 115 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 171.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-114), and 137.4 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-114). MS (ESI): mass caled. for C₂₈H₂₃Cl₂N₅O₄ 563.11, m/z found 564.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 8.11 (s, 1H), 7.48-6.95 (m, 7H), 6.58 (s, 1H), 4.09-4.02 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 1.04 (d, 3H, J=3.6 Hz), 0.63 (d, 3H, J=6.4 Hz).

Example 116 6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-115), and 9.2 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-115). MS (ESI): mass calcd. for C₃₁H₂₆Cl₂N₄O₃ 572.14, m/z found 573.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.06 (brs, 1H), 7.46-6.77 (m, 10H), 4.07-4.01 (m, 1H), 3.77 (s, 3H), 2.01-1.99 (m, 1H), 1.24-0.79 (m, 7H), 0.60 (d, 3H, J=4.4 Hz).

Example 117 2′-(2-(azetidin-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.3 mg of (S)-2′-(2-(azetidin-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (5-116), and 41.8 mg of (R)-2′-(2-(azetidin-1-yl)-4-methoxypyrimidin-5-yl)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-116). MS (ESI): mass calcd. for C₃₀H₂₇Cl₂N₇O₃ 603.15, m/z found 604.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.27 (brs, 1H), 8.22 (d, 1H, J=4.8 Hz) 7.54-6.47 (m, 6H), 4.14 (t, 4H, J=7.2 Hz), 3.87 (s, 3H), 2.36-2.32 (m, 2H), 2.22 (s, 3H), 1.08 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.6 Hz).

Example 118 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 61.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-117), and 62.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-methylpyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-117). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₃ 562, m/z found 563.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.62 (d, 1H, J=6.4 Hz), 7.57-6.48 (m, 6H), 4.15-4.12 (m, 1H), 3.96 (s, 3H), 2.63 (s, 3H), 2.22 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 119 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-118), and 24.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(ethyl(methyl)amino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-118). MS (ESI): mass calcd. for C₃₀H₂₉Cl₂N₇O₃ 605.17, m/z found 606.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.61 (brs, 1H), 8.24 (d, 1H, J=4.0 Hz), 7.55-6.47 (m, 6H), 4.16-4.15 (m, 1H), 3.89 (s, 3H), 3.69-3.68 (m, 2H), 3.15 (s, 3H), 2.21 (s, 3H), 1.23-1.16 (m, 3H), 1.09 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.2 Hz).

Example 120 6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 115.1 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-119), and 44.0 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethoxy)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-119). MS (ESI): mass caled. for Chemical Formula: C₂₉H₂₁Cl₂F₃N₄O₄, Exact Mass: 616.09, m/z found 617.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ 11.51 (brs, 1H), 7.57-7.47 (m, 2H), 7.38-7.34 (m, 2H), 7.21 (s, 1H), 7.14-7.09 (m, 3H), 7.00-6.96 (m, 2H), 4.06-4.03 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H, J=4.4 Hz), 0.62 (d, 3H, J=4.4 Hz).

Example 121 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-120), and 9.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-120). MS (ESI): mass calcd. for C₃₀H₂₆Cl₂N₆O₃ 588.14, m/z found 589.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.76 (brs, 1H), 8.54 (d, 1H, J=6.4 Hz), 7.56-6.98 (m, 7H), 4.15-4.14 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 2.07-1.99 (m, 1H), 1.35-1.08 (m, 7H), 0.66 (d, 3H, J=6.0 Hz).

Example 122 6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 13.1 mg of(S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-121), and 13.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-121). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂N₆O₃ 574.13, m/z found 575.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.55 (brs, 1H), 8.52 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.38-7.34 (m, 2H), 7.15-7.12 (m, 2H), 7.01-0.95 (m, 2H), 4.14-4.11 (m, 1H), 3.93 (s, 3H), 2.22-1.19 (m, 1H), 1.12-1.10 (m, 6H), 0.64 (d, 3H, J=6.4 Hz).

Example 123 6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 38.8 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-122), and 38.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-122). MS (ESI): mass caled. for C₂₈H₂₄Cl₂N₆O₄ 578.12, m/z found 579.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.33 (brs, 1H), 8.49 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.38-7.34 (m, 2H), 7.15-7.11 (m, 2H), 7.01 (s, 1H), 6.97-6.95 (m, 1H), 4.46 (q, 2H, J=7.2 Hz), 4.19-4.14 (m, 1H), 3.93 (s, 3H), 1.39 (t, 3H, J=7.2 Hz), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 124 6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.9 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-123), and 45.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-123). MS (ESI): mass calcd. for C₂₉H₂₆C_(l2)N₆O₄ 592.14, m/z found 593.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.58 (brs, 1H), 8.48 (s, 1H), 7.48-6.96 (m, 7H), 5.32-5.26 (m, 1H), 4.20-4.14 (m, 1H), 2.31 (s, 3H), 1.38 (d, 6H, J=6.0 Hz), 1.13 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 125 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 53.23 mg of 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-5-ethyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C₃₃H₃₃Cl₂N₅O₃ 617.20, m/z found 618.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.47 (brs, 1H), 7.95-6.47 (m, 8H), 4.11-4.08 (m, 1H), 3.78 (s, 3H), 2.74 (s, 6H), 2.66-2.61 (m, 2H), 2.22 (s, 3H), 1.238-1.071 (m, 6H), 0.68 (d, 3H, J=6.4 Hz).

Example 126 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 28.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-126), and 35.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-126). MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₆O₄ 606.15, m/z found 607.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.76 (brs, 1H), 8.50 (d, 1H, J=6.4 Hz), 7.57-6.49 (m, 6H), 5.32-5.26 (m, 1H), 4.20-4.16 (m, 1H), 3.94 (s, 3H), 2.22 (s, 3H), 1.38 (d, 6H, J=6.0 Hz), 1.09 (d, 3H, J=4.4 Hz), 0.67 (d, 3H, J=6.0 Hz).

Example 127 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-prrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 27.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-127), and 32.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-127). MS (ESI): mass calcd. for C₂₉H₂₆Cl₂N₆O₄ 592.14, m/z found 593.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.75 (brs, 1H), 8.52 (d, 1H, J=6.8 Hz), 7.567-6.486 (m, 6H), 4.46 (q, 2H, J=7.2 Hz), 4.18-4.09 (m, 1H), 3.94 (s, 3H), 2.21 (s, 3H), 1.39 (t, 3H, J=7.2 Hz), 1.09 (d, 3H, J=4.8 Hz), 0.67 (d, 3H, J=6.0 Hz).

Example 128 4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 35.3 mg of (S)-4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (S-128), and 34.5 mg of (R)-4-(6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-3-methoxybenzonitrile (R-128). MS (ESI): mass calcd. for C₂₉H₂₁Cl₂N₅O₃ 557.10, m/z found 558.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.43 (brs, 1H), 7.73-6.96 (m, 10H), 4.06-4.04 (m, 1H), 3.86 (s, 3H), 1.04 (d, 3H, J=5.6 Hz), 0.61 (d, 3H, J=5.6 Hz).

Example 129 6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.2 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-129), and 44.7 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-129). MS (ESI): mass calcd. for C₂₉H₂₁Cl₂F₃N₄O₃ 600.1, m/z found 601.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.56 (brs, 1H), 7.68-6.95 (m, 10H), 4.07-4.04 (m, 1H), 3.88 (s, 3H), 1.10 (d, 3H, J=6.0 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 130 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-130), and 30.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-fluoro-4,6-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-130). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂FN₄O₄ 594.12, m/z found 595.3 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.75 (brs, 1H), 7.44-6.60 (m, 8H), 4.00 (s, 1H), 3.86-3.77 (m, 6H), 3.86 (s, 3H), 3.81 (d, 3H, J=2.8 Hz), 2.22 (s, 3H), 1.23-1.01 (m, 3H), 0.69-0.61 (m, 3H).

Example 131 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.5 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-131), and 50.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-131). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂N₆O₄ 578, m/z found 579.3[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.80 (brs, 1H), 8.50 (d, 1H, J=1.6 Hz), 8.48 (d, 1H, J=2.0 Hz), 8.14-7.00 (m, 4H), 6.60 (s, 1H), 4.09-4.06 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J=4.0 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 132 5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 4.9 mg of (S)-5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide (S-132), and 5.4 mg of (R)-5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyridylmethylcyanide (R-132). MS (ESI): mass caled. for C₂₉H₂₂Cl₂N₆O₃ 572.11, m/z found 573.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.36 (brs, 1H), 8.69 (d, 1H, J=6.8 Hz), 8.06 (s, 1H), 7.57-6.99 (m, 6H), 4.12-4.10 (m, 1H), 3.97 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=7.6 Hz), 0.65 (d, 3H, J=7.6 Hz).

Example 133 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 63.3 mg of (S)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-133), and 66.9 mg of (R)-6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-133). MS (ESI): mass calcd. for Chemical Formula: C₂₈H₂₂Cl₂FN₅O₄ 581.10, m/z found 582.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 8.13 (s, 1H), 7.48 (d, 1H, J=7.2 Hz), 7.36-7.32 (m, 2H), 7.15 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=3.6 Hz), 7.05 (s, 1H), 6.59 (s, 1H), 4.09-4.05 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 1.10 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 134 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 38.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-134), and 40.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-134). MS (ESI): mass caled. for C₂₈H₂₅Cl₂N₇O₄ 593, m/z found 594.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.79 (brs, 1H), 8.52-8.48 (m, 2H), 7.64-7.00 (m, 4H), 4.47 (q, 2H, J=6.8 Hz), 4.21-4.18 (m, 1H), 3.99 (s, 3H), 2.27 (s, 3H), 1.39 (t, 3H, J=6.8 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 135 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-135), and 50.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-135). MS (ESI): mass calcd. for C₂₈H₂₆Cl₂N₈O₃ 592, m/z found 593.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.77 (brs, 1H), 8.50 (d, 1H, J=7.2 Hz), 8.26 (d, 1H, J=5.2 Hz), 7.62-6.99 (m, 4H), 4.17-4.14 (m, 1H), 3.90 (s, 3H), 3.19 (s, 6H), 2.26 (s, 3H), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 136 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 33.0 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-136), and 30.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-isopropoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-136). MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₆O₄ 606 m/z found 607.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.79 (brs, 1H), 8.51 (m, 2H), 7.63-7.00 (m, 4H), 5.32-5.28 (m, 1H), 4.22-4.16 (m, 1H), 3.94 (s, 3H), 2.27 (s, 3H), 1.37 (d, 6H, J=6.4 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.4 Hz).

Example 137 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 30.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-137), and 32.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-137). MS (ESI): mass caled. for C₃₀H₂₈Cl₂N₆O₄ 606, m/z found 607.4 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.77 (brs, 1H), 8.50 (d, 1H, J=6.8 Hz), 8.11 (d, 3H, J=6.4 Hz), 7.64-7.00 (m, 4H), 6.52 (s, 1H), 5.35-5.32 (m, 1H), 4.10-4.07 (m, 1H), 3.83 (s, 3H), 2.27 (s, 3H), 1.33 (d, 6H, J=6.0 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 138 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-138), and 40.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-138). MS (ESI): mass caled. for C₂₉H₂₂Cl₂F₃N₅O₃ 615.10, m/z found 616.3 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.75 (brs, 1H), 8.72 (d, 1H, J=6.8 Hz), 7.74 (s, 1H), 7.59-6.49 (m, 6H), 4.20-4.11 (m, 1H), 4.02 (s, 3H), 2.22 (s, 3H), 1.18 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 139 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.7 mg of(S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-139), and 42.1 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-139). MS (ESI): mass calcd. for Chemical Formula: C₂₉H₂₄Cl₂FN₅O₄ Exact Mass: 595.12, m/z found 596.5 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.58 (brs, 1H), 8.08 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=7.6 Hz), 7.06 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H, J=9.6 Hz), 6.56 (s, 1H), 4.40 (q, 2H, J=6.8 Hz), 4.07-4.02 (m, 1H), 3.83 (s, 3H), 1.35 (t, 3H, J=6.8 Hz), 1.11 (d, 3H, J=5.6 Hz), 0.62 (d, 3H, J=6.0 Hz).

Example 140 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-140), and 31.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-140). MS (ESI): mass caled. for C₂₉H₂₅Cl₂FN₆O₄ 610.13, m/z found 611.4 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆): δ 11.50 (brs, 1H), 8.539 (d, J=7.2 Hz, 1H), 7.57-6.48 (m, 6H), 4.86-4.61 (m, 4H), 4.19-4.16 (m, 1H), 3.96 (s, 3H), 2.145 (s, 3H), 1.09 (d, J=4.8 Hz, 3H), 0.66 (d, J=6.0 Hz, 3H).

Example 141 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 36.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-141), and 43.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-141). MS (ESI): mass caled. for C₂₈H₂₁Cl₂F₃N₆O₄ 646.11, m/z found 649.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.45 (brs, 1H), 8.60 (d, J=7.6 Hz, 1H), 7.56-6.49 (m, 6H), 5.15-5.01 (m, 2H), 4.21-4.15 (m, 1H), 3.99 (s, 3H), 2.07 (s, 3H), 1.08 (d, J=6.4 Hz, 3H), 0.66 (d, J=6.4 Hz, 3H).

Example 142 6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.9 mg of (S)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-142), and 21.6 mg of (R)-6-chloro-5′-(3-chlorophenyl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-142). MS (ESI): mass calcd. for C₂₈H₂₀Cl₂F₃N₅O₃ 601.08, m/z found 602.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.56 (brs, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H, J=8.8 Hz), 7.39-7.35 (m, 2H), 7.16-7.01 (m, 2H), 6.98-6.97 (m, 2H), 4.13-4.08 (m, 1H), 4.01 (s, 3H), 1.12 (d, 3H, J=6.4 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 143 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-143), and 23.8 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-143). MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₆O₃ 588, m/z found 589.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.76 (brs, 1H), 8.50 (d, 1H, J=8.0 Hz), 8.30 (d, 1H, J=3.6 Hz), 7.64-6.99 (m, 5H), 4.09-4.05 (m, 1H), 3.88 (s, 3H), 2.27 (s, 3H), 2.19-2.17 (m, 1H), 1.08 (d, 3H, J=6.4 Hz), 1.02-1.00 (m, 4H), 0.65 (d, 3H, J=4.0 Hz).

Example 144 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-144), and 47.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(2-methoxy-4-(trifluoromethyl)phenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-144). MS (ESI): mass caled. for C₂₉H₂₂Cl₂F₃N₅O₃ 615, m/z found 616.4[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.79 (brs, 1H), 8.51 (d, 1H, J=7.6 Hz), 7.71-7.00 (m, 7H), 4.10-4.07 (m, 1H), 3.90 (s, 3H), 2.28 (s, 3H), 1.07 (d, 3H, J=5.2 Hz), 0.66 (d, 3H, J=5.6 Hz).

Example 145 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 23.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-145), and 21.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4-cyclopropyl-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-145). MS (ESI): mass calcd. for C₃₁H₂₇Cl₂N₅O₃ 587, m/z found 588.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.71 (brs, 1H), 8.50 (d, 1H, J=7.6 Hz), 7.62-6.78 (m, 7H), 4.09-4.06 (m, 1H), 3.78 (s, 3H), 2.27 (s, 3H), 2.01-1.99 (m, 1H), 1.06-1.01 (m, 5H), 0.85-0.80 (m, 2H), 0.62 (d, 3H, J=5.6 Hz).

Example 146 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 17.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-146), and 21.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-146). MS (ESI): mass caled. for C₃₀H₂₇Cl₂N₅O₄ 591.14, m/z found 592.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.55 (brs, 1H), 7.81-6.48 (m, 8H), 4.42 (q, 2H, J=7.2 Hz), 4.13-4.11 (m, 1H), 3.88 (s, 3H), 2.22 (s, 3H), 1.38 (t, 3H, J=7.2 Hz), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.8 Hz).

Example 147 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 52.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-147), and 48.2 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-147). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂F₂N₆O₄ 628.12, m/z found 629.1 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 8.58 (d, 1H, J=7.2 Hz), 7.56-6.46 (m, 7H), 4.74-4.66 (m, 2H), 4.17-4.10 (m, 1H), 3.98 (s, 3H), 2.21 (s, 3H), 2.01-1.98 (m, 1H), 1.09 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=7.2 Hz).

Example 148 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 43.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-148), and 43.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-148). MS (ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₅ 606.14, m/z found 607.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.55-6.48 (m, 10H), 4.89 (t, J=5.2 Hz, 1H), 4.10-4.05 (m, 3H), 3.78-3.74 (m, 5H), 2.07 (s, 3H), 1.06 (d, J=5.6 Hz, 3H), 0.63 (d, J=5.6 Hz, 3H).

Example 149 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-149), and 17.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-2-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-149). MS (ESI): mass caled. for C₂₉H₃₁Cl₂N₅O₃ 589.16, m/z found 589.5[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.72 (brs, 1H), 7.84-7.81 (m, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.33-6.97 (m, 4H), 6.49 (s, 1H), 4.10-4.07 (m, 1H), 3.89 (s, 3H), 3.04-3.01 (m, 1H), 2.22 (s, 3H), 1.29 (d, 6H, J=6.8 Hz), 1.10 (d, 1H, J=6.8 Hz), 0.66 (d, 1H, J=6.8 Hz).

Example 150 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 42.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-150), and 46.0 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(difluoromethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-150). MS (ESI): mass calcd. for C₂₉H₂₃Cl₂F₂N₅O₄ 613.11, m/z found 614.5 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.65 (brs, 1H), 8.25-6.48 (m, 8H), 4.09-4.07 (m, 1H), 3.91 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=6.4 Hz).

Example 151 4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 119.4 mg of (S)-4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-151), and 105.8 mg of (R)-4-chloro-2-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-151). MS (ESI): mass calcd. for C₂₈H₂₁Cl₂N₇O₄ 589.10, m/z found 590.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.81 (brs, 1H), 8.56 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.09-7.07 (m, 1H), 4.24-4.17 (m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 1.21 (d, J=6.4 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H).

Example 152 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 41.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-152), and 45.3 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-152). MS (ESI): mass caled. for C₂₈H₂₁Cl₂F₃N₆O₃ 616 m/z found 617.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.57 (brs, 1H), 8.72 (d, 1H, J=7.2 Hz), 8.51 (d, 1H, J=6.4 Hz), 7.74 (s, 1H), 7.66-7.01 (m, 5H), 4.16-4.11 (m, 1H), 4.02 (s, 3H), 2.27 (s, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.67 (d, 3H, J=6.4 Hz).

Example 153 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-153), and 46.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2,2-difluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-153). MS (ESI): mass calcd. for C₃₀H₂₅Cl₂F₂N₅O₄ 627.12, m/z found 628.2[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.16 (d, 1H, J=5.2 Hz), 7.57-6.42 (m, 7H), 4.68-4.61 (m, 2H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 154 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 39.3 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-154), and 39.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-methoxy-6-methylpyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-154). MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₅O₃ 561.13, m/z found 562.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.35 (d, 1H, J=4.4 Hz), 7.57-6.48 (m, 7H), 4.07-4.03 (m, 1H), 3.87 (s, 3H), 2.22 (s, 3H), 1.08 (d, 3H, J=6.8 Hz), 0.64 (d, 3H, J=6.4 Hz).

Example 155 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 9.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-155), and 9.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(dimethylamino)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-155). MS (ESI): mass caled. for C₂₉H₂₇C_(l2)N₇O₃ 591.16, m/z found 594.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.79 (brs, 1H), 8.50 (s, 1H), 8.49 (d, 1H, J=5.6 Hz), 7.99-6.99 (m, 4H), 6.22 (s, 1H), 4.11-4.08 (m, 1H), 3.84 (s, 3H), 3.11 (s, 6H), 2.27 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=4.0 Hz).

Example 156 6-chloro-5′-(5-chloro-2-isopropylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 50.95 mg of 6-chloro-5′-(5-chloro-2-isopropylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₆O₄ 606.15, m/z found 607.2 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 8.53 (d, 1H, J=6.0 Hz), 7.65-7.07 (m, 6H), 4.13-4.06 (m, 1H), 3.99 (d, 3H, J=13.6 Hz), 3.96 (d, 3H, J=13.6 Hz), 3.17-3.16 (m, 1H), 1.15-1.03 (m, 9H), 0.63 (d, 3H, J=5.6 Hz).

Example 157 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-157), and 17.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(dimethylamino)-2-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-157). MS (ESI): mass caled. for C₃₀H₂₈Cl₂N₆O₃ 590.16, m/z found 591.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.60 (brs, 1H), 7.58-6.29 (m, 8H), 4.21-4.14 (m, 1H), 3.83 (s, 3H), 3.09 (s, 6H), 2.14 (s, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H).

Example 158 2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 119.4 mg of (S)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-158), and 105.8 mg of (R)-2-chloro-4-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-158). MS (ESI): mass calcd. for C₂₈H₂₁Cl₂N₇O₄ 589.10, m/z found 590.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.81 (brs, 1H), 8.52 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.17-7.09 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.13 (d, J=6.8 Hz, 3H), 0.61 (d, J=6.8 Hz, 3H).

Example 159 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 55.9 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-159), and 55.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-159). MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₆O₃ 589.14, m/z found 590.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.65 (brs, 1H), 8.56-7.00 (m, 6H), 4.17-4.14 (m, 1H), 3.94 (s, 3H), 2.27 (s, 3H), 2.20-2.19 (m, 1H), 1.13-1.07 (m, 7H), 0.68 (d, 3H, J=6.8 Hz).

Example 160 3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.4 mg of (S)-3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (S-160), and 23.3 mg of (R)-3-chloro-5-(6-chloro-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-2,6′-dioxo-3′,6′-dihydro-5′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-5′-yl)benzonitrile (R-160). MS (ESI): mass caled. for C₂₈H₂₁Cl₂N₇O₄ 589.10, m/z found 590.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.71 (brs, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.51-7.45 (m, 3H), 7.18-7.16 (m, 1H), 7.08 (s, 1H), 4.17-4.16 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.12 (d, 3H, J=5.2 Hz), 0.64 (d, 3H, J=4.8 Hz).

Example 161 6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.4 mg of (S)-6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-161), and 23.3 mg of (R)-6-chloro-5′-(3-chloro-4-(trifluoromethoxy)phenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-161). MS (ESI): mass caled. for C₂₈H₂₁Cl₂F₃N₆O₅ 648.09, m/z found 649.1 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.63 (brs, 1H), 8.52 (s, 1H), 7.61-7.50 (m, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.18-7.05 (m, 3H), 4.20-4.13 (m, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 1.11 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H).

Example 162 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 16.7 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl) amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-162), and 16.7 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-162). MS (ESI): mass calcd. for C₃₂H₃₁Cl₂N₅O₄, 619.18 m/z found 620.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.80 (brs, 1H), 7.51-6.34 (m, 9H), 4.72 (t, 1H, J=5.0 Hz), 4.13-4.10 (m, 1H), 3.76 (s, 3H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 3.02 (s, 3H), 2.22 (s, 3H), 1.05 (d, 3H, J=6.0 Hz), 0.62 (d, 3H, J=5.6 Hz).

Example 163 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 12.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-163), and 12.4 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-163). MS (ESI): mass caled. for C₃₀H₂₆Cl₂FN₅O₄ 609.13, m/z found 610.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.73 (brs, 1H), 8.13 (d, 1H, J=4.8 Hz), 7.54-6.91 (m, 6H), 6.67 (s, 1H), 4.83-4.54 (m, 4H), 4.07-4.06 (m, 1H), 3.86 (s, 3H), 2.21 (s, 3H), 1.08 (d, 3H, J=6.0 Hz), 0.65 (d, 3H, J=6.0 Hz).

Example 164

6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 14.4 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-164), and 14.5 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-164). MS (ESI): mass caled. for C₃₁H₂₉Cl₂N₅O₃, 589.16 m/z found 590.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.5 (brs, 1H), 8.43 (d, 1H, J=4.8 Hz), 7.59-6.49 (m, 7H), 4.11-4.02 (m, 1H), 3.91 (s, 3H), 3.12-3.09 (m, 1H), 2.22 (s, 3H), 1.30-1.29 (m, 6H), 1.07 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 165 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Steps similar to those in Example 1 were performed to obtain 20.0 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass caled. for C₃₀H₂₆Cl₂N₄O₅ 592.13, m/z found 593.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.80 (brs, 1H), 9.35 (s, 1H), 7.59-6.71 (m, 9H), 4.33-4.29 (m, 2H), 3.93-3.85 (m, 7H), 2.07 (s, 3H), 1.18 (d, J=6.0 Hz, 3H).

Example 166 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 31.8 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-166), and 33.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-3′-isopropyl-2′-(6-isopropyl-4-methoxypyridin-3-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-166). MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₆O₃, 590.16 m/z found 591.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.59 (brs, 1H), 8.51-8.41 (m, 2H), 7.67-7.01 (m, 5H), 4.12-4.05 (m, 1H), 3.90 (s, 3H), 3.11-3.06 (m, 1H), 2.50 (s, 3H), 1.30 (d, 6H, J=6.8 Hz), 1.09 (d, 3H, J=6.4 Hz), 0.66 (d, 3H, J=4.0 Hz).

Example 167 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-(1-hydroxymethylpropane-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Steps similar to those in Example 1 were performed to obtain 50.6 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-(1-hydroxymethylpropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass caled. for C₂₈H₂₄Cl₂N₆O₅ 594.12, m/z found 595.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.80 (brs, 1H), 9.43 (s, 1H), 8.66 (s, 1H), 7.50 (s, 1H), 7.50-6.88 (m, 5H), 4.40-4.31 (m, 2H), 4.02 (s, 6H), 3.93 (d, J=12.0 Hz), 2.05 (s, 3H), 1.24 (s, 3H).

Example 168 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Steps similar to those in Example 1 were performed to obtain 101.2 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass caled. for C₂₉H₂₅Cl₂N₅O₅ 593.12, m/z found 594.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.83 (brs, 1H), 9.42 (s, 1H), 8.25 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.28-6.88 (m, 6H), 6.64 (s, 1H), 4.34-4.30 (m, 2H), 3.94-3.91 (m, 7H), 2.06 (s, 3H), 1.21 (d, 6.8 Hz, 3H).

Example 169 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Steps similar to those in Example 1 were performed to obtain 151.1 mg of the title compound 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass caled. for C₂₇H₂₂Cl₂N₆O₃ 607.14, m/z found 608.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.83 (brs, 1H), 9.41 (s, 1H), 8.23 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.28-6.89 (m, 5H), 6.62 (s, 1H), 4.42-4.30 (m, 4H), 3.93-3.90 (m, 4H), 2.06 (s, 3H), 1.36 (t, J=6.8 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H).

Example 170 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 25.2 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-170), and 25.9 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-170). MS (ESI): mass calcd. for C₂₈H₂₄Cl₂FN₇O₄ 611.12, m/z found 612.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.65 (brs, 1H), 8.56-8.49 (m, 2H), 7.64-7.00 (m, 4H), 4.87-4.85 (m, 1H), 4.75-4.73 (m, 1H), 4.69-4.67 (m, 1H), 4.61-4.59 (m, 1H), 4.19-4.18 (m, 1H), 3.96 (s, 3H), 2.27 (s, 3H), 1.09 (d, 3H, J=6.8 Hz), 0.68 (d, 3H, J=5.6 Hz).

Example 171 6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.3 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-171), and 4.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-171). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂FN₆O₄, 596.11 m/z found 597.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.59 (brs, 1H), 8.52 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.38-7.35 (m, 2H), 7.15-7.12 (m, 2H), 7.01 (d, 1H, J=2.0 Hz), 6.98-6.95 (m, 1H), 4.87-4.59 (m, 4H), 4.18-4.15 (m, 1H), 3.95 (s, 3H), 1.12 (d, 3H, J=6.8 Hz), 0.65 (d, 3H, J=6.8 Hz).

Example 172 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 19.6 mg of (S)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-172), and 18.1 mg of (R)-6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(2-isopropyl-4-methoxypyrimidin-5-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-172). MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₆O₃ 590.19, m/z found 591.1[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.78 (brs, 1H), 8.67 (d, 1H, J=6.4 Hz), 8.29-6.48 (m, 6H), 4.08-4.06 (m, 1H), 3.98 (s, 3H), 3.14-3.11 (m, 1H), 2.22 (s, 3H), 1.34 (d, 6H, J=6.8 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.68 (d, 3H, J=6.8 Hz).

Example 173 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 20.1 mg of (S)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-173), and 19.6 mg of (R)-6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-173). MS (ESI): mass caled. for C₂₉H₂₅Cl₂FN₆O₄ 610.12, m/z found 611.2 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.81 (brs, 1H), 8.51 (dd, 1H, J¹=8.4 Hz, J²=2.4 Hz), 8.14 (d, 1H, J=5.6 Hz), 7.62-7.00 (m, 4H), 6.69 (s, 3H), 4.84-4.82 (m, 1H), 4.72-4.70 (m, 1H), 4.63-4.61 (m, 1H), 4.55-4.54 (m, 1H), 4.09-4.07 (m, 1H), 3.86 (s, 3H), 2.27 (s, 3H), 1.08 (d, 3H, J=6.4 Hz), 0.65 (d, 3H, J=6.4 Hz).

Example 174 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 37.8 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-174), and 39.0 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-174). MS (ESI): mass caled. for C₂₉H₂₃Cl₂FN₆O₃ 592.12, m/z found 593.1 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆) δ 11.75 (brs, 1H), 8.53 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.41-6.89 (m, 5H), 4.17-4.10 (m, 1H), 3.93 (s, 3H), 2.23-2.17 (m, 1H), 1.12-1.11 (m, 7H), 0.65 (d, 3H, J=6.8 Hz).

Example 175 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 45.2 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-175), and 44.9 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-175). MS (ESI): mass calcd. for C₂₈H₂₂Cl₂FN₅O₄ 581.10, m/z found 582.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 8.11 (s, 1H), 7.50 (d, 1H, J=8.4 Hz), 7.48-6.90 (m, 5H), 6.60 (s, 1H), 4.09-4.02 (m, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.11 (d, 3H, J=6.4 Hz), 0.61 (d, 3H, J=6.0 Hz).

Example 176 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 40.3 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-176), and 40.6 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-176). MS (ESI): mass caled. for C₃₀H₂₄Cl₂FN₅O₃ 591.12, m/z found 592.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 8.27 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.40-6.80 (m, 6H), 4.09-4.04 (m, 1H), 3.87 (s, 3H), 2.21-2.07 (m, 1H), 1.11 (d, 3H, J=6.4 Hz), 1.10-0.99 (m, 4H), 0.60 (d, 3H, J=6.4 Hz).

Example 177 6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 5.3 mg of (S)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-177), and 4.3 mg of (R)-6-chloro-5′-(3-chlorophenyl)-2′-(6-(2-fluoroethoxy)-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-177). MS (ESI): mass calcd. for C₂₉H₂₄Cl₂FN₅O₄ 595.12, m/z found 596.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.56 (brs, 1H), 8.11 (s, 1H), 7.49-6.95 (m, 7H), 6.68 (s, 1H), 4.83-4.53 (m, 4H), 4.09-4.02 (m, 1H), 1.11 (d, 3H, J=6.4 Hz), 0.62 (d, 3H, J=6.4 Hz).

Example 178 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Steps similar to those in Example 1 were performed to obtain 120.1 mg of the title compound 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-(1-hydroxypropan-2-yl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione. MS (ESI): mass caled. for C₂₈H₂₃Cl₂N₅O₅ 579.11, m/z found 580.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.88 (brs, 1H), 10.06 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.79-6.92 (m, 6H), 6.63 (s, 1H), 4.32-4.29 (m, 2H), 3.94 (s, 6H), 3.92-3.89 (m, 1H), 1.22 (d, 3H, J=6.8 Hz).

Example 179 5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyrimidine-2-methylcyanide

Steps similar to those in Example 1 were performed to obtain 4.3 mg of the title compound 5-(6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2,6′-dioxo-5′,6′-dihydro-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2′-yl)-4-methoxypyrimidine-2-methylcyanide. MS (ESI): mass caled. for C₂₈H₂₁Cl₂N₇O₃ Exact Mass: 573.11, m/z found 574.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.81 (brs, 1H), 8.96 (d, J=8.4 Hz, 1H), 7.59-6.50 (m, 6H), 4.27-4.22 (m, 1H), 4.05 (s, 3H), 2.21 (s, 3H), 1.10 (d, J=6.8 Hz, 3H), 0.67 (d, J=6.4 Hz, 3H).

Example 180 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione

Title compounds were obtained by steps similar to those in Example 1, and supercritical high-pressure preparative chromatography was performed to obtain 44.3 mg of (S)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (S-180), and 45.1 mg of (R)-6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione (R-180). MS (ESI): mass calcd. for C₂₈H₂₃Cl₂FN₆O₄ 596.11, m/z found 597.1 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 11.69 (brs, 1H), 8.50 (d, J=3.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.41-6.90 (m, 5H), 4.47 (q, J=6.8 Hz, 2H), 4.21-4.14 (m, 1H), 3.97 (s, 3H), 1.27 (t, J=6.4 Hz, 2H), 1.13 (d, J=6.8 Hz, 3H), 0.64 (d, J=6.4 Hz, 3H).

In order to verify the activity of the MDM2 inhibitors according to the present invention, the present invention further provides several representative Experimental Examples.

Experimental Example 1 Determination of the Inhibitory Activities of the Compounds OF THE PRESENT INVENTION ON MDM2 BY A BIOLOGICAL ASSAY METHOD

Experimental purpose: To determine the inhibitory activities of the compounds of the present invention on MDM2.

The present experiment uses the following assay methods/instruments/reagents:

Type Name (Product code) Manufacturer Plate shaker MTS2/4 IKA Microplate reader M1000pro TECAN Centrifuge Avanti J-26XP Beckman Coulter GST-MDM2 (70 μM) In-house purification Biotin-P53 (100 μM) GL Biochem Anti-GST-Tb(100×) 61GSTTLA Cisbio SA-XL665(16.67 μM) 610SAXLA Cisbio BSA B2064 Sigma AEBSF 76307 Sigma DTT 43816 Sigma PBS 20012-027 Cisbio

Experiment Subjects:

Positive control group: Compound HDM201, disclosed in patent No. 201380016617.6; synthesized in laboratory.

Experimental groups S-1 to R-180, corresponding to the compounds prepared in Examples 1-180, respectively.

Experiment Procedure: Solution Preparation:

Buffer: 1×PBS+0.1% BSA+5 mM DTT; MDM2 Buffer: Buffer+1 mM AEBSF

GST-MDM2: The final concentration is 4 nM, and it is required to formulate a 20 nM (5×) solution. A mother liquor is diluted by 3500 folds, wherein the mother liquor is 10-fold diluted first, and then 350-fold diluted.

Biotin-P53: The final concentration is 37 nM, and it is required to formulate a 185 nM (5×) solution. A mother liquor is diluted by 540.5 folds.

SA-XL665: The final concentration is 4.625 nM, and it is required to formulated a 1805 nM (4×) solution. A mother liquor is diluted by 901 folds.

Anti-GST-Tb: The final concentration is 2×, and a mother liquor is diluted by 50 folds.

MIX: GST-MDM2, Biotin-P53, SA-XL665 and Anti-GST-Tb were mixed according to a ratio of 4:4:5:5.

Sample: Preparation of a sample (10 mM in DMSO) solution: a. 3 μL sample+7 μL DMSO+20 μL DMSO were formulated to give an initial concentration of 1 mM and mixed well; b. in plate 1, twelve 5-fold serial dilutions (sequentially prepared by adding 10 μL of the last sample to 40 μL DMSO) were prepared and mixed well, individually; c. plate 2 was taken, 45 μL of Buffer was added to each well, and 5 μL of dilution at each concentration was taken from plate 1 and added to the corresponding well in plate 2 (the concentration in well 1 was 100 μM), and mixed well.

Experimental Steps:

1. 18 μL of MIX was added to a 384-well plate, and centrifugation was performed at 4500 rpm for 5 min.

2. 2 μL of sample was added correspondingly to each well, the resultant was centrifuged at 25° C. and 4500 rpm for 5 min, and shaked at 25° C. for 90 min on a shaker.

Readings were obtained from the Microplate reader, and data was processed by Graphpad Prism 6.0.

$\begin{matrix} {{Inhibition}\mspace{14mu} {rate}\mspace{14mu} {at}\mspace{14mu} {each}} \\ {{concentration}\mspace{14mu} {point}\mspace{14mu} \left( {{inh}\mspace{14mu} \%} \right)} \end{matrix} = {\frac{\begin{matrix} {{fluorescence}\mspace{14mu} {value}\mspace{14mu} {at}} \\ {{zero}\mspace{14mu} {point}\mspace{14mu} {concentration}} \end{matrix} - \begin{matrix} {{fluorescence}\mspace{14mu} {value}\mspace{14mu} {at}} \\ {{each}\mspace{14mu} {concentration}\mspace{14mu} {point}} \end{matrix}}{{fluorescence}\mspace{14mu} {value}\mspace{14mu} {at}\mspace{14mu} {zero}\mspace{14mu} {concentration}} \times 100\%}$

TABLE 1 Test results of inhibitory activities of the compounds of the present invention on MDM2 (IC₅₀: nM) Inhibition test of Experimental MDM2-P53, IC₅₀ (nM)

MDM2-PS3

₅₀ (nM) HDM201 2.50 S-1 2.21 R-1 617.89 S-2 1.13 R-2 117.50 S-3 4.92 R-3 1194.23 S-4 3.37 R-4 132.48 S-5 3.22 R-5 109.29 S-6 2.21 R-6 42.26 S-7 73.24 R-7 35972.70 S-8 3.29 R-8 329.21 S-9 2.38 R-9 332.39 S-10 2.77 R-10 116.59 S-11 1.58 R-11 257.20 S-12 3.55 R-12 367.64 S-13 2.55 R-13 120.80 S-14 1.34 R-14 460.77 S-15 1.62 R-15 107.21 S-16 3.39 R-16 570.33 S-17 3.75 R-17 49.37 S-18 1.43 R-18 158.09 S-19 34.6 R-19 NA S-20 4.39 R-20 256.30 S-21 1.34 R-21 222.76 S-22 1.10 R-22 626.74 S-23 2.80 R-23 174.99 S-24 4.40 R-24 391.92 S-25. 2.52 R-25 51.85 S-26 2.37 R-26 235.74 S-27 3.45 R-27 924.43 S-28 54.32 R-28 3109.44 S-29 1.01 R-29 93.57 S-30 3.31 S-31 60.11 R-31 1403.96 S-32 3.89 R-32 1100.34 S-33 2.47 R-33 591.54 S-34 139.47 R-34 NA S-35 23.40 R-35 NA S-36 4.67 R-66 464.19 S-37 22.01 R-37 3111.09 S-38 12.01 R-38 1115.99 S-39 3.93 R-39 1847.84 S-40 3.85 R-40 322.24 S-41 149.29 R-41 7317.32 S-42 1.51 R-42 364.49 S-43 3.28 R-43 129.78 S-44 1.18 R-44 51.11 S-45 1.72 R-45 170.63 S-46 236.27 R-46 2332.41 S-47 4.16 R-47 209.81 S-48 1.46 R-48 195.57 S-49 1.72 R-49 71.38 S-50 85.52 R-50 20410.23 S-51 4.36 R-51 547.30 S-52 0.87 R-52 540.41 S-53 0.84 R-53 3768.80 S-54 2.25 R-54 1961.81 S-55 4.25 R-55 437.30 S-56 5.19 R-56 154.99 S-57 3.04 R-57 426.50 S-58 11.42 R-58 1429.18 S-50 2.29 R-59 689.37 S-60 4.81 R..60 1072.13 S-61 1.31 R-61 135.68 S-62 1.61 R-62 252.45 S-63 1.16 R-63 537.10 S-64 11.83 R-64 1023.67 S-65 4.04 R-65 497.90 S-66 1.50 R-66 85.88 S-67 1.22 R-67 354.64 S-68 2.32 R-68 656.97 S-69 1.78 R-69 635.65 S-70 0.94 R-70 111.12 S-71 2.96 R-71 100.03 S-72 0.90 R-72 213.52 S-73 1.10 R-73 142.35 S-74 0.98 R-74 93.42 S-75 0.97 R-75 122.38 S-76 4.23 R-76 579.08 S-77 1.86 R-77 139.30 S-78 1.42 R-78 222.23 S-79 1.89 R-79 285.33 S-80 2.56 R-80 362.85 S-81 1.23 R-81 53.27 S-82 1.16 R-82 394.36 S-83 2.23 R-83 87.64 84 3.78 S-85 3.30 R-85 493.70 S-86 2.59 R-86 142.00 S-87 3.31 R-87 473.20 S-88 2.34 R-88 399.20 S-89 4.32 R-89 568.90 S-90 1.38 R-90 309.80 S-91 3.56 R-91 460.90 S-92 1.72 R-92 377.83 S-93 3.89 R-93 658.14 S-94 4.72 R-94 840.35 S-95 1.92 R-95 1668.15 S-96 1.04 R-96 150.65 S-97 3.94 R-97 5.73 S-98 1.27 R-98 1034.32 S-99 2.56 R-99 115.26 S-100 3.14 R-100 632.69 S-101 9.86 R-101 1999.88 S-102 2.01 R-102 412.91 S-103 1.81 R-103 180.98 S-104 2.26 R-104 146.16 S-105 11.20 R-105 342.96 S-106 2.59 R-106 481.33 S-107 4.55 R-107 535.69 S-108 8.87 R-108 690.54 S-109 2.34 R-109 380.99 S-110 1.60 R-110 704.44 S-111 1.52 R-111 110.36 S-112 1.15 R-112 103.77 S-113 1.25 R-113 50.54 S-114 3.20 R-114 261.25 S-115 1.30 R-115 268.55 S-116 4.18 R-116 689.19 S-117 2.15 R-117 232.73 S-118 3.51 R-118 436.15 S-119 2.39 R-119 851.01 S-120 9.01 R-120 4778.08 S-121 3.35 R-121 300.14 S-122 2.76 R-122 794.09 S-123 2.11 R-123 115.65 S-124 2.91 R-124 1314.68 125 20.79 S-126 1.52 R-126 193.43 S-127 2.76 R-127 91.04 S-128 1.09 R-128 612.42 S-129 3.84 R-129 149.30 S-130 5.59 R-130 568.03 S-131 1.17 R-131 119.79 S-132 3.60 R-132 1320.63 S-133 1.41 R-133 1109.64 S-134 2.60 R-134 322.16 S-135 1.36 R-135 422.57 S-136 2.35 R-136 1800.00 S-137 1.65 R-137 421.88 S-138 1.04 R-138 132.36 S-139 1.36 R-139 341.78 S-140 1.06 R-140 147.08 S-141 3.42 R-141 762.36 S-142 1.45 R-142 137.08 S-143 1.10 R-143 214.30 S-144 3.84 R-144 119.22 S-145 2.05 R-145 749.40 S-146 5.44 R-146 6712.03 S-147 5.89 R-147 118.69 S-148 1.58 R-148 200.92 S-149 18.49 R-149 2282.00 S-150 1.93 R-150 377.20 S-151 1410.00 R-151 5373.00 S-152 0.78 R-152 134.00 S-153 0.49 R-153 31.11 S-154 0.90 R-154 31.11 S-155 0.95 R-155 96.44 156 11.23 S-157 3.81 R-157 369.60 S-158 4.07 R-158 2203.00 S-159 2.80 R-159 467.60 S-160 5.91 R-160 5713.00 S-161 8.09 R-161 126.30 S-162 2.07 R-162 119.90 S-163 1.36 R-163 166.34 S-164 0.94 R-164 591.56 165 NA S-166 1.88 R-166 957.19 167 NA 168 NA 169 NA S-170 1.86 R-170 234.96 S-171 2.86 R-171 8830.80 S-172 4.15 R-172 408.32 S-173 1.39 R-173 528.45 S-174 4.12 R-174 515.23 S-175 1.96 R-175 522.39 S-176 1.76 R-176 320.63 S-177 2.37 R-177 108.63 178 NA 179 4.27 S-180 4.60 R-180 679.20 NA: data not available

Experimental Results:

The experimental results in Table 1 above demonstrate that:

1) The compounds of the present invention, such as the compounds prepared in Examples 1-180, have an inhibitory effect on MDM2, especially compounds with S-configuration therein have a significant inhibitory effect on MDM2.

2) Some compounds of the present invention have a better inhibitory effect on MDM2 than the positive control compound HDM201, for example, the activities of the compounds with S-configuration in Examples 2, 11, 14, 15, 18, 21, 22, 29, 42, 44, 45, 48,49, 52, 53, 61, 62,63, 66, 67, 69,70,72,73,74,75,77,78,79, 81,82, 90, 92, 95, 96,98, 102, 103, 110, 111, 112, 113, 115, 126, 128, 131, 133, 135, 137, 138, 139, 140, 142, 143, 148, 150, 152, 153, 154, 155, 163, 164, 166, 170, 173, 175 and 176 are better than that of the positive control compound HDM201.

Experimental Example 2 Determination of the Inhibition of the Mdm2 Inhibitors According to the Present Invention on the Proliferation of Human Osteosarcoma Cell Line SJSA-1 (the Same Test Subjects as Experimental Example 1)

2.1 Experimental materials: human osteosarcoma cell line SJSA-1 (Nanjing Kebai Biotechnology Co., Ltd.), DAPI (5 mg/mL, Beyotime, c1002), 4% paraformaldehyde (Ding Guo Biotech., AR-0211), 96-well plate with black transparent bottom (PE, 6005182), In Cell Analyzer 2200 (GE Healthcare).

2.2 Experiment Preparation:

2.2.1 Preparation of a culture medium for human osteosarcoma cell line SJSA-1: RPMI1640+10% FBS+1% penicillin/streptomycin

2.2.2 Preparation of a test compound solution:

a. the test compound solution with a certain concentration was taken, and diluted with the culture medium to obtain a compound solution with a final concentration of 20 μM;

b. 200 μL of a culture medium containing 0.2% DMSO (dimethyl sulfoxide) was added into H₂-H₁₀ of a 96-well plate; 300 μl of the above solution was added into H₁; and

c. 100 μL was taken out from well H₁, added into H₂, and mixed well; then 100 μl of the resultant solution was taken and added into H₃, and dilution was carried out in sequence until H₉ to obtain the 3-fold serial dilution of the test compound.

2.3 Experimental Process:

2.3.1 SJSA-1 cells were inoculated into a 96-well cell plate with black transparent bottom at 4000 cells/100 μl/well, and cultured overnight at 37° C.;

2.3.2 The above samples were added at 100 μl/well to a culture plate inoculated with cells, gently patted to mix well, and incubated at 37° C. for 72 h;

2.3.3 Fixation: the cell plate was taken out, the culture medium was removed, and 50 μL of 4% paraformaldehyde solution was added to each well to fix for 10 min;

2.3.4 50 μl of 0.1 M glycine was added to neutralize for 10 min;

2.3.5 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) twice;

2.3.6 Permeabilization: 50 μL of 0.2% TritonX-100 (Triton) was added per well, and permeabilization was carried out at room temperature for 10 min;

2.3.7 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) twice;

2.3.8 5 mg/mL DAPI stock solution was diluted at a ratio of 1:5000 (final concentration of 1 g/ml), and staining was performed at room temperature for 20 min;

2.3.9 Washing was performed with 1×PBS (phosphate buffer solution pH7.2) for three times; and

2.3.10 Scanning and analysis were performed by In cell analyzer.

2.4 Data Processing:

The inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by GraphPad Prism6.0 software to obtain the IC₅₀ value.

$\begin{matrix} {{Cell}\mspace{14mu} {relative}} \\ {{inhibition}\mspace{14mu} {rate}\mspace{14mu} (\%)} \end{matrix} = {\frac{\begin{matrix} {{fluorescence}\mspace{14mu} {value}} \\ {{of}\mspace{14mu} {control}\mspace{14mu} {group}} \end{matrix} - \begin{matrix} {{fluorescence}\mspace{14mu} {value}\mspace{14mu} {of}} \\ {{expreimental}\mspace{14mu} {group}} \end{matrix}}{{fluorescence}\mspace{14mu} {value}\mspace{14mu} {of}\mspace{14mu} {control}\mspace{14mu} {group}} \times 100\%}$

TABLE 2 Inhibitory activities of the compounds of the present invention on proliferation of human osteosarcoma cell line SJSA-1 Examples IC₅₀ (nM) HDM201 91.31 S-1 39.62 R-1 16660.88 S-2 7.40 R-2 2772.00 S-3 173.71 R-3 16271.55 S-4 7.92 R-4 2188.17 S-5 25.44 R-5 1595.07 S-6 6.20 R-6 1766.00 S-7 1271.50 R-7 NA S-8 10.33 R-8 2293.00 S-9 7.39 R-9 2817.23 S-10 124.27 R-10 2169.08 S-11 1.67 R-11 1508.07 S-12 5.27 R-12 2441.56 S-13 5.95 R-13 1124.55 S-14 63.47 R-14 5378.16 S-15 10.87 R-15 840.33 S-16 3557.71 R-16 20057.44 S-17 201.10 R-17 1311.66 S-18 13.91 R-18 1615.66 S-19 352.22 R-19 NA S-20 48.08 R-20 4005.08 S-21 62.19 R-21 5232.02 S-22 7.46 R-22 6954.13 S-23 1.24 R-23 353.78 S-24 4.17 R-24 872.23 S-25 8.83 R-25 265.16 S-26 22.23 R-26 3646.55 S-27 119.33 R-27 NA S-28 1289.92 R-28 NA S-29 196.37 R-29 10856.23 S-30 58.10 R-30 NA S-31 1584.88 R-31 3575.10 S-32 10.09 R-32 8197.15 S-33 9.70 R-33 4885.16 S-34 618.96 R-34 NA S-35 257.65 R-35 NA S-36 72.27 R-36 3176.49 S-37 14.16 R-17 2439.34 S-38 14.74 R-38 NA S-39 1183.40 R-39 NA S-40 14.08 R-40 3086.90 S-41 1205.42 R-41 NA S-42 5.60 R-42 4555.29 S-43 563.67 R-43 NA S-44 11.95 R-44 1332.43 S-45 6.20 R-45 4307.06 S-46 5981.97 R-46 NA S-47 14.02 R-47 3851.55 S-48 16 84 R-48 3630.98 S-49 5.92 R-49 1486.41 S-50 1315.42 R-50 8427.52 S-51 62.56 R-51 9516.69 S-52 466.77 R-52 22436.03 S-53 213.39 R-53 77439.40 S-54 468.31 R-54 NA S-55 117.29 R-55 9939.33 S-36 83.85 R-56 3481.69 S-57 11.78 R-57 3958.52 S-58 50.75 R-58 5892.75 S-59 262.70 R-59 NA S-60 NA R-60 NA S-61 5.50 R-61 135.68 S-62 10.54 R-62 4357.85 S-63 77.62 R-63 NA S-64 725.96 R-64 NA S-65 NA R-65 NA S-66 39.59 R-66 3861.83 S-67 20.76 R-67 8492.33 S-68 1702.99 R-68 NA S-69 2.29 R-69 6584.81 S-70 73.64 R-70 4205.60 S-71 291.56 R-71 7017.36 S-72 5.90 R-72 3480.88 S-73 250.87 R-73 NA S-74 7.85 R-74 1839.65 S-75 9.84 R-75 3040.51 S-76 308.66 R-76 NA S-77 535.23 R-77 NA S- 78 7.88 R-78 1363.64 8-79 72.44 R-79 NA S-80 16.85 R-80 NA S-81 82.79 R-81 1603.25 S-82 7.43 R-82 NA S-83 6.21 R-83 588.54 84 2606.15 S-85 40.18 R-85 2187.76 S-86 21.18 R-86 NA S-87 11.12 R-87 7345.13 S-88 77.27 R-88 NA S-89 43.25 R-89 NA S-90 254.68 R-90 NA S-91 14.42 R-91 993.12 S-92 19.86 R-92 4875.28 R-91 NA S-94 309.03 R-94 NA S-95 49.55 R-95 NA S-96 25.29 R-96 NA S-97 167.49 R-97 395.80 S-98 56.10 R-98 NA S-99 34.20 R-99 1472.31 S-100 1210.60 R-100 NA S-101 48.53 R-101 NA S-102 57.41 R-102 NA S-103 40.46 R-103 2426.61 S-104 266.07 R-104 6886.52 S-105 243.22 R-105 NA S-106 33.50 R-106 NA S-107 114.82 R-107 3235.93 S-108 28.77 R-108 NA S-109 54.58 R-109 8203.52 S-110 77.98 R-110 NA S-111 13.03 R-111 561.05 S-112 90.57 R-112 NA S-113 26.73 R-113 2172.70 S-114 10.12 R-114 1870.68 S-115 3357.38 R-115 26.92 S-116 212.81 R-117 NA S-117 14.42 R-117 NA S-118 107.15 R-118 NA S-119 20.00 R-119 NA S-120 363.92 R-120 NA S-121 66.99 R-121 NA S-122 117.21 R-122 NA S-123 321.37 R-123 NA S-124 129.41 R-124 NA 125 60.26 S-126 79.62 R-126 1592.21 S-127 83.18 R-127 1570.36 S-128 144.88 R-128 NA S-129 146.22 R-129 NA S-130 NA R-130 NA S-131 46.34 R-131 NA S-132 163.68 R-132 NA S-133 99.77 R-133 NA S-134 82.22 R-134 NA S-135 96.16 R-135 NA S-136 108.39 R-136 NA S-137 65.92 R-137 NA S-138 75.68 R-138 NA S-139 50.70 R-139 NA S-140 81.47 R-140 862.98 S-141 73.62 R-141 NA S-142 137.72 R-142 NA S-143 24.89 R-143 6223.00 S-144 100.92 R-144 2449.06 S-145 28.25 R-145 NA S-146 67.76 R-146 NA S-147 271.02 R-147 5741.16 S-148 71.78 R-148 NA S-149 153.46 R-149 NA S-150 80.53 R-150 5701.63 S-151 NA R-151 NA S-152 79.80 R-152 NA S-153 21.99 R-153 NA S-154 22.03 R-154 NA S-155 14.59 R-155 1524.05 156 NA S-157 16.67 R-157 1798.87 S-158 549.54 R.158 NA S-159 34.20 R-159 5333.35 S-160 350.75 R-160 NA S-161 557.18 R-161 NA S-162 14.93 R-162 781.63 S-163 125.60 R-163 NA S-164 16.79 R-164 NA 165 NA S-166 38.11 R-166 NA 167 NA 168 NA 169 NA S-170 130.62 R-170 NA S-171 379.31 R-171 NA S-172 53.33 R-172 NA S-173 216.77 R-173 NA S-174 93.50 R-174 NA S-175 49.20 R-175 NA S-176 28.84 R-176 NA S-177 420.72 R-177 4246.20 178 NA 179 52.72 S-180 56.75 R-180 2172.70 NA: data not available

Experimental Results:

The experimental results of Table 2 above demonstrate that:

1) The compounds of the present invention, such as the compounds prepared in Examples 1-180, have an inhibitory effect on the human osteosarcoma cell line SJSA-1, and especially the compounds with S-configuration therein have a significant inhibitory effect on the human osteosarcoma cell line SJSA-1.

2) Some compounds of the present invention have a better inhibitory effect on the human osteosarcoma cell line SJSA-1 than the positive control compound HDM201, for example, the inhibitory effects on the human osteosarcoma cell line SJSA-1 of the compounds with S-configuration in Examples 2, 4,6, 9,11, 12, 13, 15, 22, 23, 24, 25, 32, 33, 42, 45, 49, 61, 69, 72, 74, 75, 78, 82, 83, 86, 89, 91, 92, 96, 98, 99, 101, 102, 103, 106, 108, 110, 113, 114, 115, 119, 121, 126, 127, 131, 137, 138, 139, 141, 143, 145, 146, 153, 154, 155, 157, 159, 162, 164, 166, 172, and 176 are better than that of the positive control compound HDM201.

Experimental Example 3 Determination of the Pharmacokinetics of the Mdm2 Inhibitors of the Present Invention in Mice

3.1 Experimental Summary

ICR mice were used as the test animals, and the concentrations of the drugs in plasma of mice at different time points after intravenous administration and intragastric administration of the representative compounds were measured by a LC/MS/MS method, so as to study the pharmacokinetic behavior of the compounds of the present invention in mice and evaluate the pharmacokinetic characteristics thereof.

3.2 Experimental Scheme

3.2.1 Test Drugs:

Some compounds prepared in Examples 1-180 of the present invention.

The control drug HDM201 was prepared by the method disclosed in patent No. CN104203952A.

3.2.2 Test Animals:

Healthy adult ICR mice, male, 6-9 weeks old, weighing 20-30 g, purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd., Animal Production License No.: SCXK (HU) 2013-0016

3.2.3 Preparation of Test Drugs

Intragastric or intravenous administration: an appropriate amount of sample was weighed, dissolved in 5% DMSO+40% PEG400+55% (10% HP-β-CD in Saline) to prepare a 0.5 mg/ml solution for intragastric or intravenous administration.

3.2.4 Administration of Test Drugs

Intravenous administration: for each test compound, 3 male ICR mice were administered intravenously at a dose of 2 mg/kg and an administration volume of 1 ml/kg after fasting overnight.

Intragastric administration: for each test compound, 3 male ICR mice were administered intragastrically at a dose of 5 mg/kg and an administration volume of 5 ml/kg after fasting overnight.

3.3 Experimental Operation

Before administration and 0.083 h, 0.167 h, 0.25 h, 0.33 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration, approximately 0.2 mL blood was collected via jugular vein puncture, the obtained blood was anticoagulated with heparin sodium, and placed on ice after collection, and the blood was centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 min, and 4° C.). The collected plasma was stored at −80° C. before analysis. The plasma sample was analyzed by LC-MS/MS, and the sample was pretreated by protein precipitation method. The linear range of sample analysis was 1 to 2000 ng/ml. The lowest quantification limit was 1 ng/mL. WinNonlin (Pharsight, USA) was used to calculate the following pharmacokinetic parameters: area under the curve AUC_((0-t)), area under the curve AUC_((0-∞)), half-life t_(1/2), retention time MRT_((0-∞)), blood drug concentration C_(max), time taken to reach the peak blood drug concentration T_(max), bioavailability F, apparent volume of distribution V_(z), and clearance rate CL.

3.4 Results of Pharmacokinetic Data

TABLE 3 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of HDM201 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 101 0.67 0.08 585.03 622.13 713.62 0.66 0.96 2717.30 2802.63 102 0.53 0.08 605.51 573.66 619.30 0.59 0.75 2456.27 3229.47 103 0.67 0.08 459.85 520.23 600.29 0.68 0.98 3231.81 3331.71 Mean 0.62 0.083 550.13 572.01 644.40 0.64 0.90 2801.79 3121.27 SD 0.08 0.000 78.85 50.97 60.69 0.04 0.13 394.61 280.65 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 201 1.34 0.50 408.75 1058.75 1078.76 1.94 2.09 202 0.74 0.50 584.08 797.19 818.45 1.04 1.15 203 1.24 0.50 715.01 1522.78 1539.76 1.82 1.91 Mean 1.11 0.50 569.28 1126.24 1145.66 1.60 1.72 78.76 SD 0.32 0.00 153.66 367.47 365.28 0.49 0.50 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 4 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-1 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 301 1.21 0.08 307.80 532.69 548.82 1.33 1.52 6380.69 3644.18 302 1.00 0.08 329.89 725.28 736.92 1.31 1.41 3917.79 2713.99 303 0.98 0.08 336.17 843.53 855.63 1.34 1.43 3308.82 2337.47 Mean 1.07 0.083 324.62 700.50 713.79 1.33 1.45 4535.77 2898.55 SD 0.13 0.000 14.90 156.90 154.71 0.01 0.06 1626.50 672.62 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 629.23 1822.90 1834.25 1.94 1.99 402 1.98 1.00 471.21 1944.41 2088.41 2.60 3.17 403 1.92 1.00 92.81 241.17 330.15 1.79 3.13 Mean 1.64 1.00 397.75 1336.16 1417.60 2.11 2.76 76.30 SD 0.54 0.00 275.65 950.23 950.30 0.43 0.67 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%\,}$

TABLE 5 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-2 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 501 1.11 0.08 492.38 1362.57 1392.31 1.51 1.64 2291.83 1436.46 502 0.84 0.50 477.30 1554.01 1564.61 1.47 1.51 1552.17 1278.27 503 0.93 1.00 456.11 1477.86 1494.93 1.47 1.54 1804.36 1337.86 Mean 0.96 0.528 475.26 1464.81 1483.95 1.48 1.56 1882.79 1350.86 SD 0.13 0.459 18.22 96.38 86.68 0.02 0.07 376.01 79.90 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 601 1.45 2.00 655.97 3165.38 3254.89 2.89 3.09 602 1.83 1.00 729.77 3883.23 4100.77 2.87 3.28 603 1.50 2.00 804.59 4136.52 4259.08 2.76 2.97 Mean 1.59 1.67 730.11 3728.38 3871.58 2.84 3.12 101.81 SD 0.21 0.58 74.31 503.75 539.90 0.07 0.16 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 6 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-9 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 701 1.26 0.08 1403.26 3334.44 3452.37 1.47 1.68 1055.16 579.31 702 1.40 0.08 1274.58 3650.23 3830.08 1.58 1.88 1054.38 522.18 703 1.16 0.08 1643.99 4107.04 4214.93 1.47 1.63 793.38 474.50 Mean 1.27 0.083 1440.61 3697.23 3832.46 1.51 1.73 967.64 525.33 SD 0.12 0.000 187.52 388.44 381.29 0.06 0.13 150.91 52.48 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 801 1.57 2.00 1366.47 6319.30 6555.06 2.65 2.92 802 1.44 1.00 2009.05 8692.39 8911.44 2.60 2.78 803 1.22 1.00 1914.07 6976.33 7048.92 2.68 2.75 Mean 1.41 1.33 1763.20 7329.34 7505.14 2.64 2.82 79.30 SD 0.18 0.58 346.84 1225.29 1242.67 0.04 0.09 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 7 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of compound S-11 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) V_(Z) CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 101 1.15 0.50 1376.51 3578.38 3680.24 1.43 1.61 0.91 9.06 102 2.09 0.50 1519.69 4225.58 4820.40 1.81 2.70 1.25 6.92 103 1.15 0.50 1302.60 3169.84 3250.24 1.40 1.55 1.02 10.26 Mean 1.46 0.500 1399.60 3657.93 3916.96 1.55 1.95 1.06 8.74 SD 0.54 0.000 110.37 532.35 811.41 0.23 0.65 0.17 1.69 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 201 2.18 1.00 1645.73 8018.78 8771.68 2.96 3.66 202 1.55 1.00 1573.02 8536.56 8816.41 2.87 3.11 203 1.33 2.00 2144.69 11568.40 11784.98 2.92 3.05 Mean 1.69 1.33 1787.81 9374.58 9791.02 2.92 3.27 102.51 SD 0.44 0.58 311.20 1917.46 1726.96 0.04 0.34

TABLE 8 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-23 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 101 1.57 0.08 3640.21 6625.30 7084.65 1.55 1.99 0.64 4.71 102 1.86 0.08 3779.72 9462.95 10504.31 1.78 2.46 0.51 3.17 103 1.33 0.08 3040.32 6172.76 6427.71 1.50 1.75 0.60 5.19 Mean 1.59 0.083 3486.75 7420.34 8005.55 1.61 2.07 0.58 4.35 SD 0.26 0.000 392.86 1783.37 2188.77 0.15 0.36 0.07 1.05 PO- 5 mg/kg t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F*

h h ng/mL h*ng/mL h*ng/mL h h % 201 1.15 1.00 2050.29 7235.20 7315.60 2.35 2.43 202 0.98 1.00 3316.65 9122.66 9163.57 2.02 2.05 203 1.52 0.50 2730.39 7675.41 7881.03 2.08 2.29 Animal 1.22 0.83 2699.11 8011.09 8120.07 2.15 2.26 43.18 number 0.27 0.79 633.76 987.49 946.89 0.18 0.19 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 9 Pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-32 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h mL/kg mL/h/kg 901 1.23 0.25 2766.01 4699.29 4854.66 1.32 1.53 730.20 411.98 902 1.44 0.50 2451.28 7199.84 7627.51 1.61 1.97 542.87 262.21 903 1.26 0.08 1902.13 3859.04 4004.98 1.29 1.53 908.33 499.38 Mean 1.31 0.278 2373.14 5252.72 5495.32 1.41 1.68 727.14 391.19 SD 0.11 0.210 437.21 1737.80 1894.44 0.17 0.25 182.75 119.94 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 1001 2.89 1.00 1578.70 6017.39 7102.68 2.79 4.22 1002 1.51 1.00 3356.31 10704.89 11027.74 2.24 2.48 1003 2.07 1.00 2518.33 8458.06 9168.53 2.48 3.14 Mean 2.16 1.00 2484.45 8393.45 9099.65 2.50 3.28 63.92 SD 0.69 0.00 889.29 2344.42 1963.44 0.27 0.88 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 10 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-44 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.91 0.08 951.21 2987.84 3364.67 1.77 2.56 1.64 9.91 302 1.79 0.08 872.25 2506.41 2766.34 1.71 2.35 1.86 12.05 303 1.92 0.08 826.58 2703.63 3052.47 1.82 2.61 1.82 10.92 Mean 1.87 0.083 883.35 2732.63 3061.16 1.77 2.51 1.77 10.96 SD 0.08 0.000 63.05 242.03 299.26 0.05 0.14 0.12 1.07 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.56 1.00 1357.96 7904.41 8959.71 3.17 4.17 402 1.77 1.00 1097.85 5161.46 5447.83 2.81 3.22 403 1.65 2.00 1204.30 6287.89 6556.64 3.08 3.38 Mean 2.00 1.33 1220.04 6451.26 6988.07 3.02 3.59 94.43 SD 0.49 0.58 130.77 1378.76 1795.24 0.19 0.51 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 11 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-45 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) V_(Z) CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.01 0.25 779.74 1865.23 1895.22 1.36 1.45 1.54 17.59 302 1.00 0.08 882.75 2072.07 2103.04 1.35 1.44 1.37 15.85 303 1.05 0.08 765.75 1793.27 1825.35 1.34 1.45 1.65 18.26 Mean 1.02 0.139 809.41 19110.19 1941.20 1.35 1.45 1.52 17.23 SD 0.02 0.096 63.90 144.74 144.44 0.01 0.01 0.14 1.24 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.17 0.50 1590.61 5862.67 6346.49 2.56 3.21 402 1.54 1.00 1355.63 5315.63 5471.40 2.53 2.75 403 1.87 1.00 1169.32 4196.04 4431.71 2.56 2.99 Mean 1.86 0.83 1371.85 5124.78 5416.53 2.55 2.99 107.31 SD 0.32 0.29 211.11 849.55 958.57 0.02 0.23

TABLE 12 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-61 IV- 2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.09 0.08 2994.43 4640.74 4724.28 1.21 1.32 0.67 7.06 302 1.00 0.08 3249.64 3583.88 3626.86 0.99 1.07 0.80 9.19 303 1.15 0.08 3244.96 5346.76 5483.62 1.26 1.42 0.60 6.08 Mean 1.08 0.083 3163.00 4523.79 4611.59 1.15 1.27 0.69 7.44 SD 0.07 0.000 146.02 887.24 933.50 0.14 0.18 0.10 1.59 PO- 5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 3.58 0.25 2434.93 2462.65 2768.24 1.57 2.85 402 2.71 0.50 2489.40 4960.30 5500.70 2.03 3.00 403 2.98 0.25 1772.67 3162.34 3530.81 1.91 3.00 Mean 3.09 0.33 2232.33 3528.43 3933.25 1.84 2.95 31.20 SD 0.44 0.14 399.01 1288.44 1409.98 0.24 0.09 ${\,^{*}F} = {\frac{{AUC}_{{({0 - t})}{({PO})}} \times {Dose}_{({IV})}}{{AUC}_{{({0 - t})}{({IV})}} \times {Dose}_{({PO})}} \times 100\%}$

TABLE 13 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-69 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.83 0.08 6038.43 52203.96 52314.11 4.30 4.35 0.16 0.64 302 2.88 0.50 5977.53 53093.43 53217.23 4.38 4.44 0.16 0.63 303 4.02 0.08 5141.60 50006.21 50659.35 4.62 4.95 0.23 0.66 Mean 3.24 0.222 5719.19 51767.87 52061.56 4.43 4.58 0.18 0.64 SD 0.67 0.241 501.13 1589.14 1297.22 0.17 0.32 0.04 0.02 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.24 2.00 7627.20 69211.96 69264.13 4.92 4.94 402 2.28 2.00 10867.97 106563.84 106654.00 5.03 5.04 403 2.03 2.00 11828.43 85266.27 85298.58 4.46 4.47 Mean 2.18 2.00 10107.87 87014.02 87072.23 4.80 4.82 67.23 SD 0.13 0.00 2201.34 18737.18 18757.93 0.30 0.31

TABLE 14 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-72 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.16 1.00 3686.88 14847.37 17305.95 1.96 2.98 0.36 1.93 302 1.39 0.08 4634.53 11456.75 11918.88 1.53 1.78 0.34 2.80 303 1.23 0.08 4839.23 11802.83 12174.58 1.52 1.71 0.29 2.74 Mean 1.59 0.389 4386.88 12702.32 13799.80 1.67 2.16 0.33 2.49 SD 0.50 0.529 614.80 1865.71 3039.10 0.25 0.71 0.03 0.49 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.54 0.50 7867.58 51286.19 51351.03 3.95 3.98 402 1.13 0.50 7160.86 23996.12 24161.28 2.18 2.23 403 1.47 1.00 6289.71 26941.23 27586.31 2.66 2.84 Mean 1.72 0.67 7106.05 34074.52 34366.20 2.93 3.01 107.30 SD 0.73 0.29 790.36 14978.31 14808.64 0.91 0.89

TABLE 15 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-96 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 3.36 0.08 3438.41 6719.85 6815.93 2.62 2.99 1.42 4.89 302 0.93 0.08 2982.34 3109.78 3157.25 0.90 1.00 0.85 10.56 303 1.07 0.08 3353.43 3206.41 3250.65 0.90 0.99 0.95 10.25 Mean 1.79 0.083 3258.06 4345.35 4407.95 1.47 1.66 1.07 8.57 SD 1.37 0.000 242.53 2056.95 2085.90 1.00 1.16 0.31 3.19 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.69 0.25 3921.65 6327.28 6705.00 1.66 2.15 402 2.06 0.50 2400.19 6993.90 7471.54 2.42 2.97 403 2.58 0.50 5236.64 13010.63 15115.19 2.30 3.61 Mean 2.11 0.42 3852.83 8777.27 9763.91 2.13 2.91 80.80 SD 0.44 0.14 1419.48 3681.32 4650.17 0.41 0.73

TABLE 16 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-98 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.93 0.08 3405.07 11177.15 12596.27 1.82 2.60 0.44 2.65 302 1.43 0.08 3672.74 10025.81 10533.19 1.55 1.86 0.39 3.16 303 1.17 0.08 3789.06 8869.53 9108.92 1.43 1.60 0.37 3.66 Mean 1.51 0.083 3622.29 10024.16 10746.13 1.60 2.02 0.40 3.16 SD 0.39 0.000 196.90 1153.81 1753.40 0.20 0.52 0.04 0.51 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.31 4.00 3835.13 37288.31 37324.50 5.36 5.38 402 2.12 2.00 3420.72 18064.52 19691.36 3.17 3.82 403 2.30 2.00 2943.86 23330.62 23352.18 4.72 4.74 Mean 2.24 2.67 3399.90 26227.82 26789.35 4.41 4.65 104.66 SD 0.11 1.15 446.00 9933.98 9305.51 1.12 0.78

TABLE 17 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-103 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 4.11 1.00 1333.49 5508.40 8771.81 2.33 5.91 1.35 3.80 302 2.89 1.00 1332.61 10460.62 10483.52 4.16 4.21 0.79 3.18 303 2.71 1.00 1045.99 4009.87 5119.53 2.05 3.75 1.53 6.51 Mean 3.24 1.000 1237.36 6659.63 8124.95 2.85 4.62 1.22 4.50 SD 0.77 0.000 165.73 3375.95 2739.88 1.15 1.13 0.38 1.77 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.84 2.00 2382.42 10967.55 11688.42 3.08 3.54 402 1.72 4.00 2344.01 13078.28 14231.55 3.36 3.93 403 2.23 4.00 3008.06 19872.62 19888.79 4.45 4.47 Mean 1.93 3.33 2578.16 14639.49 15269.59 3.63 3.98 87.93 SD 0.27 1.15 372.80 4653.29 4197.58 0.73 0.46

TABLE 18 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-115 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 0.90 0.08 4136.98 2987.42 3011.30 0.82 0.87 0.87 11.07 302 0.90 0.08 2997.99 2575.46 2591.81 0.90 0.94 1.00 12.86 303 0.80 0.08 2549.96 2278.66 2289.66 0.79 0.82 1.01 14.56 Mean 0.87 0.083 3228.31 2613.85 2630.92 0.84 0.88 0.96 12.83 SD 0.06 0.000 818.20 355.93 362.40 0.05 0.06 0.08 1.74 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.07 0.50 2135.46 3655.37 3672.50 1.37 1.41 402 1.19 1.00 834.66 2355.30 2377.88 2.13 2.20 403 1.12 4.00 601.29 2985.59 3066.25 3.22 3.39 Mean 1.12 1.83 1190.47 2998.75 3038.87 2.24 2.33 45.89 SD 0.06 1.89 826.66 650.14 647.74 0.93 1.00

TABLE 19 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-121 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 5.50 0.08 3887.60 24572.30 25488.79 5.26 6.22 0.62 1.31 302 5.25 0.08 3346.18 28379.48 29352.82 5.15 6.03 0.52 1.14 303 5.09 0.08 3576.94 26953.62 27749.72 5.04 5.79 0.53 1.20 Mean 5.28 0.083 3603.57 26635.14 27530.44 5.15 6.01 0.56 1.21 SD 0.21 0.000 271.69 1923.47 1941.33 0.11 0.21 0.06 0.09 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 3.09 2.00 4920.31 40051.63 40259.72 4.96 5.08 402 3.34 4.00 4835.52 43063.09 43407.01 5.27 5.45 403 3.14 4.00 4714.57 40782.54 41032.91 5.40 5.54 Mean 3.19 3.33 4823.47 41299.09 41566.55 5.21 5.36 62.02 SD 0.13 1.15 103.40 1570.77 1640.10 0.23 0.24

TABLE 20 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-131 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 0.90 0.08 1997.01 1776.79 1788.59 0.94 0.98 1.45 18.64 302 0.76 0.08 1776.22 1261.09 1264.23 0.71 0.73 1.73 26.37 303 0.98 0.08 2021.33 1579.23 1594.10 0.90 0.96 1.78 20.91 Mean 0.88 0.083 1931.52 1539.04 1548.98 0.85 0.89 1.65 21.97 SD 0.11 0.000 135.04 260.19 265.08 0.12 0.14 0.18 3.97 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 1438.00 3743.48 3765.68 1.90 1.95 402 1.28 1.00 1853.01 5902.77 6003.28 2.27 2.40 403 1.47 1.00 1794.96 6839.45 7052.50 2.45 2.68 Mean 1.26 1.00 1695.32 5495.23 5607.15 2.21 2.34 142.82 SD 0.22 0.00 224.73 1587.71 1678.83 0.28 0.37

TABLE 21 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-133 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.22 0.08 2055.95 2904.29 3022.24 1.20 1.45 1.16 11.03 302 1.07 0.08 2980.85 4602.71 4699.55 1.18 1.31 0.66 7.09 303 1.13 0.08 2521.09 3187.22 3247.82 1.05 1.17 1.01 10.26 Mean 1.14 0.083 2519.30 3564.74 3656.54 1.14 1.31 0.94 9.46 SD 0.08 0.000 462.45 909.97 910.29 0.08 0.14 0.26 2.09 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.15 1.00 1569.92 6074.68 6148.80 2.34 2.43 402 1.05 1.00 1489.30 4282.62 4314.80 2.17 2.22 403 1.04 1.00 2195.02 5953.82 5994.87 2.05 2.10 Mean 1.08 1.00 1751.41 5437.04 5486.16 2.19 2.25 61.01 SD 0.06 0.00 386.28 1001.58 1017.34 0.15 0.17

TABLE 22 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-134 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.47 0.08 3408.57 6534.27 6880.52 1.50 1.83 0.61 4.84 302 0.93 0.08 3518.10 5015.80 5060.18 1.17 1.23 0.53 6.59 303 1.07 0.25 4224.01 7289.25 7419.12 1.28 1.39 0.42 4.49 Mean 1.15 0.14 3716.89 6279.77 6453.27 1.32 1.48 0.52 5.31 SD 0.28 0.10 442.58 1159.90 1236.14 0.17 0.31 0.10 1.12 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.38 0.50 3905.15 9716.82 9926.06 2.04 2.21 402 1.54 0.25 3059.53 7889.97 8123.13 2.04 2.28 403 1.43 0.50 1591.65 4859.23 4978.41 2.21 2.40 Mean 1.45 0.42 2852.11 7488.67 7675.87 2.10 2.29 47.70 SD 0.08 0.14 1170.61 2453.53 2503.96 0.10 0.10

TABLE 23 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-135 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.03 0.08 3314.60 6495.01 7378.29 1.70 2.57 0.80 4.52 302 1.65 0.08 3896.05 7270.82 7835.48 1.60 2.09 0.61 4.25 303 1.78 0.08 3518.53 7341.09 7977.92 1.66 2.21 0.64 4.18 Mean 1.82 0.083 3576.39 7035.64 7730.56 1.65 2.29 0.68 4.32 SD 0.19 0.000 295.01 469.51 313.28 0.05 0.25 0.10 0.18 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.87 1.00 2159.84 9385.38 9974.62 2.64 3.12 402 1.27 1.00 2014.04 7012.03 7126.47 2.19 2.32 403 1.34 1.00 2249.28 9412.84 9616.11 2.43 2.59 Mean 1.49 1.00 2141.05 8603.42 8905.73 2.42 2.67 48.91 SD 0.33 0.00 118.74 1378.25 1551.28 0.22 0.41

TABLE 24 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-137 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.57 0.08 5653.28 10168.14 10938.18 1.50 1.97 0.41 3.05 302 1.68 0.08 5261.76 8963.80 9736.77 1.51 2.06 0.50 3.42 303 2.79 0.08 5945.51 15555.08 15581.80 2.84 2.88 0.52 2.14 Mean 2.01 0.083 5620.19 11562.34 12085.58 1.95 2.30 0.48 2.87 SD 0.67 0.000 343.08 3509.85 3086.83 0.77 0.50 0.05 0.66 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.85 0.50 5883.71 15390.44 16193.31 2.28 2.70 402 1.98 0.50 5542.83 16097.34 17159.38 2.31 2.84 403 1.69 0.50 6791.01 14779.57 15367.65 2.03 2.35 Mean 1.84 0.50 6072.52 15422.45 16240.12 2.21 2.63 53.35 SD 0.15 0.00 645.15 659.47 896.78 0.16 0.25

TABLE 25 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-138 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 3.81 0.08 1828.27 6387.52 6445.45 4.19 4.42 1.70 5.17 302 4.03 0.08 2169.08 6061.48 6126.90 4.04 4.32 1.90 5.44 303 4.29 0.08 2002.99 3427.99 5237.36 2.03 5.54 2.37 6.36 Mean 4.04 0.083 2000.11 5292.33 5936.57 3.42 4.76 1.99 5.66 SD 0.24 0.000 170.42 1622.77 626.13 1.21 0.68 0.34 0.63 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.69 4.00 1239.88 7428.81 9151.03 3.56 5.12 402 2.74 2.00 1475.55 7494.57 8818.35 3.19 4.51 403 2.74 1.00 1466.48 8147.05 9514.89 3.27 4.52 Mean 2.72 2.33 1393.97 7690.15 9161.42 3.34 4.72 58.12 SD 0.02 1.53 133.53 397.06 348.38 0.19 0.35

TABLE 26 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-140 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-t)) MRT_((0-t)) MRT_((0-t)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 2.67 0.08 5215.16 11628.12 14758.73 1.94 3.62 0.52 2.26 302 1.70 0.08 4542.99 9144.58 9903.12 1.58 2.11 0.50 3.37 303 4.19 0.08 6627.89 19456.40 19918.23 3.73 4.34 0.61 1.67 Mean 2.86 0.083 5462.01 13409.70 14860.03 2.42 3.36 0.54 2.43 SD 1.25 0.000 1064.14 5381.82 5008.33 1.15 1.14 0.06 0.86 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 2.19 2.00 4254.74 22556.48 24737.64 2.97 3.69 402 1.54 2.00 5947.01 26053.96 26994.24 2.67 2.93 403 2.38 1.00 4972.85 23914.34 26699.24 2.97 3.85 Mean 2.04 1.67 5058.20 24174.92 26143.71 2.87 3.49 72.11 SD 0.44 0.58 849.36 1763.24 1226.59 0.18 0.49

TABLE 27 Some pharmacokinetic parameters of ICR mice after intravenous and oral administration of S-159 IV-2 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) Vz CL number h h ng/mL h*ng/mL h*ng/mL h h L/kg mL/min/kg 301 1.86 0.08 2457.53 4501.92 4960.27 1.52 2.19 1.08 13.44 302 1.22 0.08 2540.90 3595.54 3718.50 1.23 1.45 0.95 17.93 303 1.75 0.08 2591.90 4456.51 4834.16 1.45 2.00 1.05 13.79 Mean 1.61 0.083 2530.11 4184.66 4504.31 1.40 1.88 1.02 15.05 SD 0.34 0.000 67.83 510.70 683.45 0.15 0.38 0.07 2.50 PO-5 mg/kg Animal t_(1/2) T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) MRT_((0-t)) MRT_((0-∞)) F* number h h ng/mL h*ng/mL h*ng/mL h h % 401 1.03 1.00 1438.00 3743.48 3765.68 1.90 1.95 402 1.28 1.00 1853.01 5902.77 6003.28 2.27 2.40 403 1.47 1.00 1794.96 6839.45 7052.50 2.45 2.68 Mean 1.26 1.00 1695.32 5495.23 5607.15 2.21 2.34 52.53 SD 0.22 0.00 224.73 1587.71 1678.83 0.28 0.37

Experimental results: the experimental results in tables 3 to 27 above show that: after oral intragastric administration at a dose of 5 mg/kg, the bioavailability of HDM201 is 78.76%, and the AUC_(0-t) is 1126.24 h*ng/ml; after oral intragastric administration at a dose of 5 mg/kg, the representative compound S-1 of the present invention has an AUC_(0-t) of 1336.16 h*ng/mL, and a half-life of 1.64 hr, which are better than the corresponding parameters of HDM201; the compound S-2 has a bioavailability of 101.81%, an AUC_(0-t) of 3728.38 h*ng/mL, and a half-life of 1.59 hr, which are better than the corresponding parameters of HDM201; the compound S-9 has an AUC_(0-t) of 7329.34 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-11 has a bioavailability of 102.51%, an AUC_(0-t) of 9374.58 h*ng/mL, and a half-life of 1.69 hr, which are better than the corresponding parameters of HDM201; the compound S-23 has an AUC_(0-t) of 8011.09 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-32 has an AUC_(0-t) of 8393.45 h*ng/mL, and a half-life of 2.16 hr, which are better than the corresponding parameters of HDM201; the compound S-44 has a bioavailability of 94.43%, an AUC_(0-t) of 6451.26 h*ng/mL, and a half-life of 2.00 hr, which are better than the corresponding parameters of HDM201; the compound S-45 has a bioavailability of 107.31%, an AUC_(0-t) of 5124.78 h*ng/mL, and a half-life of 1.86 hr, which are better than the corresponding parameters of HDM201; the compound S-61 has an AUC_(0-t) of 3528.43 h*ng/mL, and a half-life of 3.09 hr, which are better than the corresponding parameters of HDM201; the compound S-69 has an AUC_(0-t) of 87014.02 h*ng/mL, and a half-life of 2.18 hr, which are better than the corresponding parameters of HDM201; the compound S-72 has a bioavailability of 107.30%, an AUC_(0-t) of 34074.52 h*ng/mL, and a half-life of 1.72 hr, which are better than the corresponding parameters of HDM201; the compound S-96 has an AUC_(0-t) of 8777.27 h*ng/mL, and a half-life of 2.11 hr, which are better than the corresponding parameters of HDM201; the compound S-98 has a bioavailability of 104.66%, an AUC_(0-t) of 26227.82 h*ng/mL, and a half-life of 2.24 hr, which are better than the corresponding parameters of HDM201; the compound S-103 has an AUC_(0-t) of 14639.49 h*ng/mL, and a half-life of 1.93 hr, which are better than the corresponding parameters of HDM201; the compound S-115 has an AUC_(0-t) of 2998.75 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-121 has an AUC_(0-t) of 41299.09 h*ng/mL, and a half-life of 3.19 hr, which are better than the corresponding parameters of HDM201; the compound S-131 has an AUC_(0-t) of 5495.23 h*ng/mL, and a half-life of 1.26 hr, which are significantly better than the corresponding parameters of HDM201; the compound S-133 has an AUC_(0-t) of 5437.04 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-134 has an AUC_(0-t) of 7488.67 h*ng/mL, and a half-life of 1.45 hr, which are better than the corresponding parameters of HDM201; the compound S-135 has an AUC_(0-t) of 8603.42 h*ng/mL, which is better than the corresponding parameter of HDM201; the compound S-137 has an AUC_(0-t) of 15422.45 h*ng/mL, and a half-life of 1.84 hr, which are better than the corresponding parameters of HDM201; the compound S-138 has an AUC_(0-t) of 7690.15 h*ng/mL, and a half-life of 2.72 hr, which are better than the corresponding parameters of HDM201; the compound S-140 has an AUC_(0-t) of 24174.92 h*ng/mL, and a half-life of 2.04 hr, which are better than the corresponding parameters of HDM201; and the compound S-159 has an AUC_(0-t) of 5495.23 h*ng/mL, which is better than the corresponding parameter of HDM201.

The above contents show and describe the basic principles, main features and advantages of the present invention. A person skilled in the art should understand that the present invention is not limited by the above-mentioned Examples. The above-mentioned Examples and the description only describe the principles of the present invention. It is obvious to a person skilled in the art that there will be various variations and improvements in the present invention, without departing from the spirit and scope of the present invention, and these variations and improvements fall within the claimed protection scope of the present invention. The claimed protection scope of the present invention is defined by the appended claims and their equivalents. 

1.-17. (canceled)
 18. A compound of structural formula I:

wherein, R₁ is linear or branched C₁-C₅ alkyl, C₃-C₅ cycloalkyl or

R₂ is H or (C₁-C₆ alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₃ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, tetrahydropyrrol-1-yl, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH₃ and —OH; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; or R₃ is selected from:

R₅ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —C(O)OCH₃, —CH₂CN, tetrahydropyrrol-1-yl, azetidin-1-yl, and azetidin-1-yl substituted with one or more —OH, or with —CH₃ and —OH; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; or R₅ is selected from:

R₆ is selected from halogen, halomethyl, methyl and cyano; R₇ is selected from H, (C₁-C₆) alkyl and halogen; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; wherein: R₈ is selected from —OH, —OCH₃, —NH₂, —NHMe, —NMe₂, —NHCOMe, —NHCOH and methanesulfonyl; R₉ is H or alkyl having 1 to 4 carbon atoms; R₁₀ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl and methanesulfonyl; wherein R₁₁ is selected from —OCH₃, —CH₂CH₃, —OH, halomethoxy and H; R₁₂ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₁₃ is halogen or alkyl having 1 to 4 carbon atoms; R₁₄ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₁₅ is selected from NH₂, —C(O)OH, —NH(C(O)—CH₃) and —C(O)—NH(CH₃); R₁₆ is selected from H, (C₁-C₆) alkyl and halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; and R₁₇ is selected from —C(O)—NR₉(R₁₀), (C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl, and —C(O)O(C₁-C₆)alkyl; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; and X₁ is oxygen or sulfur; Y, X₂, V and W are each independently carbon or nitrogen; wherein when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —CN, halogen, (C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀, and —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl and methanesulfonyl; or a stereoisomer, an enantiomer, a diastereomer, a racemate, a mesomer, a cis/trans isomer, a tautomer, an isotopic variant of the compound of structural formula I, or any combination thereof; or a pharmaceutical salt, a solvate, a hydrate, a polymorph or a prodrug of the compound of structural formula I, the stereoisomer, the enantiomer, the diastereomer, the racemate, the mesomer, the cis/trans isomer, the tautomer, the isotopic variant or their combination; or a hydrate of the pharmaceutical salt.
 19. The compound according to claim 18, wherein R₃ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH₃ and —OH; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; and R₅ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, haloalkyl, haloalkoxy, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —C(O)OCH₃, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH or with —CH₃ and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from alkoxy having 1 to 4 carbon atoms, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl.
 20. The compound according to claim 19, wherein R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl, and

R₂ is H or (C₁-C₆ alkyl), wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₃ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH, or with —CH₃ and —OH; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; or R₃ is selected from:

R₅ is a 5- or 6-membered aromatic ring or aromatic heterocycle which is unsubstituted or substituted by 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —C(O)-morpholin-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, —CH₂CN, azetidin-1-yl and azetidin-1-yl substituted with one or more —OH or with —CH₃ and —OH; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy and ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; or R₅ is selected from:

R₆ is selected from chlorine, fluorine, bromine, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl and cyano; R₇ is selected from H, (C₁-C₆) alkyl and halogen; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₈ is selected from —OH, —OCH₃, —NH₂, —NHMe, —NMe₂, —NHCOMe, —NHCOH or methanesulfonyl; R₉ is H, methyl or ethyl; R₁₀ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl and methanesulfonyl; R₁₁ is selected from —OCH₃, —CH₂CH₃, —OH, —OCF₃, —OCHF₂, —OCH₂F and H; R₁₂ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₁₃ is selected from halogen, methyl and ethyl; R₁₄ is H or (C₁-C₆) alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₁₆ is selected from H, (C₁-C₆) alkyl and halogen; wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; and R₁₇ is selected from —C(O)—NR₉(R₁₀), (C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl, and —C(O)O(C₁-C₆)alkyl; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl, and when present, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —CN, halogen, (C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀, or —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted by 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl or methanesulfonyl.
 21. The compound according to claim 18, wherein R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, cyclobutyl, cyclopentyl,

R₂ is H or methyl; R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl, —CH₂CN and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃, —CH₂CN and tetrahydropyrrol-1-yl, wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₆ is chlorine or cyano; R₇ is hydrogen; X₁ is oxygen; X₂, V and W are each carbon; and Y is nitrogen or carbon; wherein when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀ and —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄) alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; wherein R₉ is selected from H, methyl and ethyl; and R₁₀ is H or (C₁-C₆)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄) alkyl and methanesulfonyl.
 22. The compound according to claim 21, wherein R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl and —CH₂CN, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; and R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃ and —CH₂CN, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl.
 23. The compound according to claim 22, wherein R₃ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)O—(C₁-C₄)alkyl and tetrahydropyrrol-1-yl; and R₅ is a 6-membered aromatic ring or aromatic heterocycle substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —CH₂CN, —CH₂C(O)NR₉R₁₀, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R₉)—C(O)—(C₁-C₄)alkyl, —NR₉R₁₀, —CH₂NR₉R₁₀, —C(O)OCH₃ and tetrahydropyrrol-1-yl.
 24. The compound according to claim 21, wherein Y is carbon or nitrogen; wherein when Y is nitrogen, R₄ is absent; and wherein when Y is carbon, R₄ is selected from H, hydroxyl, —O—(C₁-C₆)alkyl, —C(O)OH, —CH₂C(O)OH, —CH₂C(O)NR₉R₁₀ and —C(O)O—(C₁-C₆)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₁ is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl; R₂ is H; R₃ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl and —NR₉R₁₀; wherein the alkyl or cycloalkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₅ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, —O—(C₃-C₆)cycloalkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, hydroxyalkoxy, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl and —NR₉R₁₀; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₆ is chlorine; R₇ is hydrogen; X₁ is oxygen; and X₂, V and W are each carbon; wherein R₉ is selected from H, methyl and ethyl; and R₁₀ is H or (C₁-C₆)alkyl, wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl and methanesulfonyl.
 25. The compound according to claim 24, wherein R₃ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents, the substituent independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀ and —NR₉R₁₀; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀ and methanesulfonyl; R₅ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀ and —NR₉R₁₀; wherein the alkyl is optionally substituted with 0 to 3 substituents independently selected from methoxy, ethoxy, hydroxyl, sulfhydryl, halogen, —C(O)OH, —C(O)O—(C₁-C₄)alkyl, —C(O)NR₉R₁₀, —NR₉R₁₀, and methanesulfonyl; and R₁₀ is selected from H, methyl, ethyl and 1-hydroxyethyl.
 26. The compound according to claim 25, wherein R₃ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted by 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl and —NR₉R₁₀; R₅ is a pyridine, pyridone, pyrimidine, pyrazine or pyridazine ring each substituted with 1 to 3 substituents independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —O-cyclopropyl, hydroxyethoxy, halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂F, —CN, —C(O)NR₉R₁₀, —CH₂NR₉R₁₀, —CH₂NR₉—C(O)R₁₀, —C(O)OH, —CH₂NR₉R₁₀, tetrahydropyrrol-1-yl and —NR₉R₁₀; and R₁₀ is H, methyl or ethyl.
 27. The compound according to claim 18, selected from:


28. The compound according to claim 27, selected from: 6-chloro-5′-(3-chlorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2,4-dimethoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(4-(dimethylamino)-2-methoxyphenyl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-3′-isopropyl-2′-(4-isopropyl-2-methoxyphenyl)-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(3-chloro-5-fluorophenyl)-2′-(2,4-dimethoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(6-ethoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(6-cyclopropyl-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(3-chlorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-fluorophenyl)-2′-(4,6-dimethoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-ethoxy-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(6-isopropoxy-4-methoxypyridin-3-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; 6-chloro-5′-(5-chloro-2-methylphenyl)-2′-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione; and 6-chloro-5′-(5-chloro-2-methylpyridin-3-yl)-2′-(2-cyclopropyl-4-methoxypyrimidin-5-yl)-3′-isopropyl-3′H-spiro[dihydroindole-3,4′-pyrrolo[3,4-d]imidazole]-2,6′(5′H)-dione.
 29. The compound according to claim 18, wherein the compound is in the S configuration.
 30. A method of synthesizing a compound according to claim 18, wherein Y is N, the method comprising:

(1) subjecting compound 1 and compound 2 to a substitution and rearrangement reaction to synthesize compound 3; (2) subjecting compound 3 and compound 4 to a cyclization reaction to construct an imidazole ring to obtain compound 5; (3) brominating compound 5 with N-bromosuccinimide to obtain compound 6; (4) subjecting compound 6 and compound 7 to low-temperature lithiation with lithium diisopropylamide to obtain compound 8; (5) subjecting compound 8 and compound 9 to an ammonolysis reaction to obtain compound 10; (6) subjecting compound 10 to an acidification and dehydration reaction to obtain compound 11; and (7) subjecting compound 11 and an aryl or heteroaryl borate or boronic acid to a Suzuki coupling reaction to obtain a compound according to claim 18, wherein Y is N.
 31. A method of synthesizing a compound according to claim 18, wherein Y is C, the method comprising:

(1) subjecting compound 1 and compound 2 to a substitution reaction to synthesize compound 3; (2) brominating compound 3 with N-bromosuccinimide to obtain compound 4; (3) subjecting compound 4 and compound 5 to low-temperature lithiation with lithium diisopropylamide to obtain compound 6; (4) subjecting compound 6 and compound 7 to an ammonolysis reaction to obtain compound 8; (5) subjecting compound 8 to an acidification and dehydration reaction to obtain compound 9; and (6) subjecting compound 9 and an aryl or heteroaryl boronic acid to a Suzuki coupling reaction to obtain a compound according to claim 18, wherein Y is C.
 32. A pharmaceutical composition comprising a compound according to claim 18 and a pharmaceutically acceptable excipient.
 33. The pharmaceutical composition of claim 32, further comprising one or more therapeutically active agents.
 34. The pharmaceutical composition of claim 33, wherein the therapeutically active agent is an anti-proliferative agent.
 35. A method for treating a disease mediated by the activity of MDM2 and/or MDM4, the method comprising administering an effective amount of a compound according to claim
 18. 36. The method according to claim 35, wherein the disease is cancer, a tumor disease or a disease associated with dysregulation of cell cycle. 